Substituted thiazoles useful for treatment of diabetes

ABSTRACT

Compounds of formula ##STR1## where the substituents are as defined herein, are disclosed, which compounds are useful in the treatment of diabetes and obesity, among other uses.

This is a divisional of application Ser. No. 629,509, filed Dec. 18,1990, now U.S. Pat. No. 5,219,852 which is a continuation of applicationSer. No. 413,358, filed Nov. 20, 1989 (abandoned), which is a divisionalof application Ser. No. 093,415, filed Sep. 4, 1987, now U.S. Pat. No.4,886,814, which is a continuation of application Ser. No. 024,934,filed Mar. 12, 1987 (abandoned).

European Patent Application EP-A-5848, published on Dec. 12, 1979discloses certain substituted thiazoles and oxazoles which may berepresented by the formula: ##STR2## in which X represents an oxygen orsulphur atom, Alk represents a straight-chained or branched alkylenegroup with 2 to 5 carbon atoms, and n represents the number 0 or 1.These compounds are said to have valuable pharmacological properties, inparticular a stimulating action on cardiac β-receptors, for example apositive inotropic or positive chronotropic action.

DESCRIPTION OF THE INVENTION

It has now been found, surprisingly, that new substituted thiazoles andoxazoles of the formula ##STR3## their optical isomers (or"enantiomers") and diastereomers (or "diastereoisomers"), since thesenew compounds contain one or more optically active carbon atoms, andtheir acid addition salts have valuable properties.

Thus, the lactams of formula I, in which R₃ and R₄ taken togetherrepresent --CH₂ CO--, their optical isomers and diastereomers, representvaluable intermediates for the preparation of the morpholines of formulaI, in which R₃ and R₄ together represent an ethylene (--CH₂ CH₂ --)group. These morpholines and the other compounds of formula I (exceptingthe lactams), the optical isomers, diastereomers and acid addition saltsthereof, in particular the physiologically tolerated acid addition saltswith inorganic or organic acids, have quite different pharmacologicalproperties than as noted above in said EP-A-5848 application, namely, anaction on the metabolism, preferentially a blood sugar lowering and bodyfat reducing action as well as causing a reduction in the levels ofatherogenic β-lipoproteins VLDL and LDL. In addition, some of the abovementioned compounds also have an anabolic action.

In the above formula I:

A is n-alkylene of 2 to 3 carbons, optionally mono- or di-substitutedwith methyl or ethyl,

X is oxygen or sulphur,

R₁ is selected from the group consisting of hydrogen, halo of atomicweight less than 80 (i.e., fluoro, chloro and bromo), trifluoromethyl,alkyl, phenyl, piperidino, amino, alkylamino, dialkylamino,alkanoylamino and benzoylamino,

R₂ is hydrogen or alkyl,

R₃ is hydrogen or alkyl, optionally substituted in the 2- or 3-positionby hydroxyl,

R₄ is selected from the group consisting of hydrogen, alkyl, optionallysubstituted by a member selected from the group consisting of phenyl,carboxyl, alkoxycarbonyl, cyano, and, in the 2- or 3-position, hydroxyl,and alkenyl,

R₃ together with R₄ is selected from the group consisting ofalkoxycarbonylmethylene, --CH₂ CH₂ --, --CH₂ CO-- and --COCH₂ --, and

R₅ is selected from the group consisting of hydroxyl, alkoxy, carboxyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkoxy having 1 to 6 carbons and substituted by a terminal memberselected from carbonyl, alkylaminocarbonyl and dialkylaminocarbonyl,alkoxy having 2 to 7 carbons and substituted by a terminal memberselected from the group consisting of hydroxyl, alkoxy, phenylalkoxy,amino, alkylamino, dialkylamino, pyrrolidino, piperidino andhexamethyleneimino and ethylene optionally substituted by alkyl andsubstituted by a terminal member selected from the group consisting ofcarboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl anddialkylaminocarbonyl,

wherein said alkyl, alkoxy and alkanoyl each contain, unless indicatedotherwise, 1 to 3 carbons, and said alkenyl contains 3 to 5 carbons.

Typical examples included in said defined symbols are:

for A: the ethylene, 1-methyl-ethylene, 2-methyl-ethylene,1-ethyl-ethylene, 2-ethyl-ethylene, 1,2-dimethyl-ethylene,1,1-dimethyl-ethylene, 1,1-diethyl-ethylene, 1-ethyl-1-methyl-ethylene,2,2-dimethyl-ethylene, 2,2-diethyl-ethylene, 2-ethyl-2-methyl-ethylene,n-propylene, 1-methyl-n-propylene, 2-methyl-n-propylene,3-methyl-n-propylene, 1-ethyl-n-propylene, 2-ethyl-n-propylene,3-ethyl-n-propylene, 1,1-dimethyl-n-propylene, 1,1-diethyl-n-propylene,2,3-dimethyl-n-propylene, 3,3-dimethyl-n-propylene or3-ethyl-3-methyl-n-propylene group,

for R₁ : the hydrogen, fluorine, chlorine or bromine atom, thetrifluoromethyl, methyl, ethyl, n-propyl, isopropyl, phenyl, amino,methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino,di-n-propylamino, N-ethyl-methylamino, N-ethyl-n-propylamino,piperidino, formylamino, acetamino, propionylamino or benzoylaminogroup,

for R₂ : the hydrogen atom or the methyl, ethyl, n-propyl or isopropylgroup,

for R₃ : the hydrogen atom, the methyl, ethyl, n-propyl, isopropyl,2-hydroxy-ethyl, 2-hydroxy-propyl or 3-hydroxy-propyl group or

for R₃ together with R₄ : the ethylene group in which one methylenegroup can be replaced by a carbonyl group, the methoxycarbonylmethylene,ethoxycarbonylmethylene, n-propoxycarbonylmethylene orisopropoxycarbonylmethylene group,

for R₄ : the hydrogen atom, the methyl, ethyl, n-propyl, isopropyl,benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenyl-n-propyl, carboxymethyl,1-carboxyethyl, 2-carboxyethyl, 3-carboxy-n-propyl,methoxycarbonylmethyl, ethoxycarbonylmethyl n-propoxycarbonylmethyl,1-ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl,3-isopropoxycarbonyl-n-propyl, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl,3-cyano-n-propyl, 2-hydroxy-ethyl, 3-hydroxy-n-propyl, allyl,buten-2-yl, buten-3-yl or penten-2-yl group, and

for R₅ : the hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, carboxyl,methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, aminocarbonyl,methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl,dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl,N-ethyl-methylaminocarbonyl, N-ethyl-isopropylaminocarbonyl,2-hydroxy-ethoxy, 3-hydroxy-n-propoxy, 4-hydroxy-n-butoxy,5-hydroxy-n-pentoxy, 6-hydroxy-n-hexoxy, 7-hydroxy-n-heptoxy,2-methoxy-ethoxy, 2-ethoxy-ethoxy, 2-n-propoxy-ethoxy,3-ethoxy-n-propoxy, 4-methoxy-n-butoxy, 6-ethoxy-n-hexoxy,2-phenethoxy-ethoxy, 2-amino-ethoxy, 2-methylamino-ethoxy,2-dimethylamino-ethoxy, 2-isopropylamino-ethoxy,2-di-n-propylamino-ethoxy, 2-(1-pyrrolidino)ethoxy,2-(1-piperidino)ethoxy, 2-(1-hexamethyleneimino)ethoxy,3-amino-n-propoxy, 6-amino-n-hexoxy, 7-methylamino-n-heptoxy,3-diethylamino-n-propoxy, 3-(1-piperidino)-n-propoxy,4-dimethylamino-n-butoxy, carboxymethoxy, 2-carboxyethoxy,3-carboxy-n-propoxy, 4-carboxy-n-butoxy, methoxycarbonylmethoxy,2-methoxycarbonyl-ethoxy, 6-methoxycarbonylhexoxy,ethoxycarbonylmethoxy, 2-ethoxycarbonyl-ethoxy,3-ethoxycarbonyl-n-propoxy, n-propoxycarbonylmethoxy,2-isopropoxycarbonyl-ethoxy, 4-n-propoxycarbonyl-n-butoxy,aminocarbonylmethoxy, 2-aminocarbonyl-ethoxy, 4-aminocarbonyl-n-butoxy,methylaminocarbonylmethoxy, 2-methylaminocarbonyl-ethoxy,dimethylaminocarbonylmethoxy, 2-dimethyl-aminocarbonyl-ethoxy,4-dimethylaminocarbonyl-n-butoxy, diethylaminocarbonylmethoxy,2-diethyl-aminocarbonyl-ethoxy, 2-di-n-propylaminocarbonyl-ethoxy,2-carboxyethenyl, 2-carboxy-1-methyl-ethenyl,2-carboxy-2-methyl-ethenyl, 2-carboxy-1-ethyl-ethenyl,2-carboxy-1-n-propyl-ethenyl, 2-methoxycarbonylethenyl,2-methoxy-carbonyl-1-methyl-ethenyl, 2-ethoxycarbonylethenyl,2-ethoxy-carbonyl-1-methylethenyl or 2-isopropoxycarbonylethenyl group.

In addition to the compounds mentioned in the Examples, the followingcompounds which are embraced by the above-mentioned formula I may alsobe mentioned, by way of example:

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-dimethylamino-thiazol-4-yl)ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methylamino-thiazol-4-yl)ethanamine.

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-amino-thiazol-4-yl)ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-5-yl)ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-4-methyl-thiazol-5-yl)-ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-methoxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-methyl-2-methoxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-methyl-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-allyl-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-(2-phenylethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-cyanomethyl-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2(4-Methlaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-dimethylamino-thiazol-4-yl)-ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methylamino-thiazol-4-yl)-ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-5-yl)ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-5-yl)ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl[-2-hydroxy-2-(2-trifluoromethyl-4-methyl-thiazol-5-yl)ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-oxazol-4-yl)ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-methoxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-N-methyl-2-methoxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-N-methyl-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-methoxy-2-(2-methyl-thiazol-4-yl)ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-N-allyl-2-hydroxy-2-(2-trifluoromethyl-thiazol4-yl)ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-N-(2-phenylethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-N-cyanomethyl-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)ethyl]-2-hydroxy-2-(2-trifluoromethyl-triazol-4-yl)ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)ethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine,

N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-(6-Hydroxyhexoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine,

N-[2-(4-(2-(1-Piperidino)ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethanamine,

N-[2-(4-(2-Methylaminoethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-22-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine,

N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-(2-methyl-thiazol-4-yl)morpholine,

N-[2-(4-Carbomethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine,

N-[2-(4-(2-(1-Piperidino)ethoxy)phenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine,

Methyl3-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-5-(2-methyl-thiazol-4-yl)-2-oxazolidinecarboxylate,

Methyl3-[2-(4-aminocarbonylmethoxyphenyl)-1-methylethyl]-5-(2-methyl-thiazol-4-yl)-2-oxazolidinecarboxylate,

Methyl3-[2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethyl]-5-(2-methyl-thiazol-4-yl)-2-oxazolidinecarboxylate,

Methyl 3-[2-(4-carbomethoxymethoxyphenyl)ethyl]-5-(2-trifluoromethyl-thiazol-4-yl) -2-oxazolidine carboxylate,

Methyl3-[2-(4-aminocarbonylmethoxyphenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidine-carboxylate,

Methyl3-[2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate,

Methyl3-[2-(4-carboxymethoxyphenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate,

Methyl3-[2-(4-(6-hydroxyhexoxy)phenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidine-carboxylate,

Methyl3-[2-(4-(2-hydroxyethoxy)phenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidine-carboxylate,

Methyl3-[2-(4-(2-methylaminoethoxy)phenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidine-carboxylate,

Methyl 3-[2-(4-(2-(1-piperidino)ethoxy)phenyl-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate,

Methyl3-[3-(4-carboxamidophenyl)-1-methylpropyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-methoxy-2-(2-chloro-thiazol-4-yl)ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-methyl-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-methyl-2-methoxy-2-(2-chloro-thiazol-4-yl)ethanamine,

MethylN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-5-(2-chloro-thiazol-4-yl)-2-oxazolidinecarboxylate,

N-[2-(4-(2-Ethoxyethoxy)phenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanamine,

Methyl 3-[2-(4-(2-carbomethoxy-1-methylethenyl)phenyl)1-methylethyl]-5-(2-chloro-thiazol-4-yl)-2-oxazolidine carboxylate,

N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-oxazol-4-yl)ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-methyl-oxazol-4-yl)morpholine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-methyl-oxazol-4-yl)ethanamine,

Methyl3-[2-(4-(2-carbomethoxy-1-methylethenyl)phenyl)-1-methyl-ethyl]-5-(2-methyl-oxazol-4-yl)-2-oxazolidinecarboxylate,

N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-N-methyl-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-methoxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2-methoxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-6-one,

N-[2(4-Carboxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-6-one,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-chloro-thiazol-4-yl)morpholin-6-one,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-6-one,

N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-Hydroxyethoxy)phenyl)-1-methylethyl]-N-carbethoxymethyl-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-(2-Methoxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-(2-Methoxyethoxy)phenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine,

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-N-methyl-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

N-[2-(4-(2-Ethoxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanamine,

N-[2-(4-(2-Ethoxyethoxy)phenyl)-1-methylethyl]-2-(2-chloro-thiazol-4-yl)morpholine,

N-[2-(4-(2-Phenethoxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanamine,

N-[2-(4-(2-Phenethoxyethoxy)phenyl)-1-methylethyl]-2-(2-chloro-thiazol-4-yl)morpholine,

N-[2-(4-(2-Phenethoxyethoxy)phenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanamineand

Methyl3-[2-(4-(2-ethoxyethoxy)phenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate,

their optical isomers, their diastereomers and their acid additionsalts.

However, preferred compounds of formula I are those in which

A is ethylene or n-propylene, optionally substituted by methyl,

X is oxygen or sulphur

R₁ is selected from the group consisting of hydrogen, chloro, alkyl,trifluoromethyl, phenyl, amino, methylamino, dimethylamino, piperidino,acetylamino and benzoylamino,

R₂ is hydrogen or methyl,

R₃ is hydrogen or methyl,

R₄ is selected from the group consisting of hydrogen, methyl,2-hydroxyethyl, carboxymethyl, carbethoxymethyl, and benzyl,

R₃ together with R₄ is selected from the group consisting ofmethoxycarbonylmethylene, --CH₂ CH₂ --, and --COCH₂ --, and

R₅ is selected from the group consisting of hydroxy, methoxy, carboxy,methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, carboxymethoxy,methoxycarbonylmethoxy, ethoxycarbonylmethoxy, aminocarbonylmethoxy,methylaminocarbonylmethoxy, 2-hydroxyethoxy, 2-ethoxy-ethoxy,2-phenethoxyethoxy, 2-aminoethoxy, 2-methylaminoethoxy,2-(1-piperidino)-ethoxy, 6-hydroxy-n-hexoxy and2-carbomethoxy-1-methylethenyl,

and the optical isomers and diastereomers thereof and physiologicallyacceptable acid addition salts thereof with inorganic or organic acids.

However, particularly preferred compounds are those or the generalformula ##STR4## in which R₁ is selected from the group consisting ofchloro, methyl and trifluoromethyl,

R₃ is hydrogen,

R₄ is selected from the group consisting of hydrogen, methyl,2-hydroxyethyl and carbethoxymethyl,

R₃ together with R₄ is ethylene or methoxycarbonylmethylene,

R₅ is selected from the group consisting of carboxymethoxy,carbomethoxymethoxy, ethoxycarbonylmethoxy, aminocarbonylmethoxy,methylaminocarbonylmethoxy, 2-methylaminoethoxy, 2-hydroxyethoxy and2-carbomethoxy-1-methylethenyl,

and the optical isomers and diastereomers thereof and physiologicallyacceptable acid addition salts thereof with inorganic or organic acids.

The new compounds of formula I are obtained according to the followingprocesses:

a) reaction of a compound of the general formula ##STR5## with acompound of the general formula ##STR6## (in which R₁ to R₃, A and Xeach are as hereinbefore defined,

Z₁ represents a nucleophilic leaving group, and

Z₂ represents a R₄ --NH group, or

Z₂ represents a nucleophilic leaving group, and

Z₁ represents a R₄ --NH group, R₄ being as hereinbefore defined, and

R₅ ' has the meanings mentioned hereinbefore for R₅, it not beingpossible, however, for R₅ ' to represent any of thealkoxycarbonylmethoxy groups mentioned hereinbefore, and it beingpossible for a carboxyl, amino or alkylamino group contained in theradical R₅ to be protected by a protecting group), and, whereappropriate, subsequent elimination of a protecting group which has beenused.

Examples of suitable nucleophilic leaving groups are halogen atoms orsulphonyloxy groups, for example a chlorine, bromine or iodine atom, themethane-sulphonyloxy, p-toluenesulphonyloxy or ethoxy-sulphonyloxygroup,

and examples of suitable protecting groups for a carboxyl group are thebenzyl, tert.butyl, tetrahydropyranyl, trimethylsilyl, benzyloxymethyl,2-chloroethyl or methoxyethyl groups, or a phenacyl group such as thebenzoylmethyl group,

and examples of suitable protecting groups for an amino or alkylaminogroup are the acetyl, benzoyl, tert.butoxycarbonyl, benzyloxycarbonyl,ethoxycarbonyl or benzyl groups.

The reaction is expediently carried out in a solvent or solvent mixture,such as acetone, diethyl ether, methylformamide, dimethylformamide,dimethyl sulphoxide, benzene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran, dioxane or in an excess of the compounds offormulae II and/or III which are used and, where appropriate, in thepresence of an acid-binding agent, for example an alcoholate such aspotassium tert.butylate, an alkali metal hydroxide such as sodium orpotassium hydroxide, an alkali metal carbonate such as potassiumcarbonate, an alkali metal amide such as sodamide, an alkali metalhydride such as sodium hydride, a tertiary organic base such astriethylamine, N,N-diisopropylethylamine or pyridine, it also beingpossible for the latter simultaneously to serve as solvent, or of areaction accelerator such as potassium iodide, depending on thereactivity of the radical which can undergo nucleophilic exchange,expediently at temperatures between 0° and 150° C., preferably attemperatures between 50° and 120° C., for example at the boiling pointof the solvent used. However, it is also possible to carry out thereaction without a solvent. However, the reaction is particularlyadvantageously carried out in the presence of a tertiary organic base orof an excess of the amine of formula II or III which is used.

The subsequent elimination, where appropriate, of a protecting groupwhich has been used is preferably carried out by hydrolysis in anaqueous solvent, for example in water, isopropanol/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas hydrochloric acid or sulphuric acid, or in the presence of an alkalimetal base such as sodium hydroxide or potassium hydroxide, attemperatures between 0° and 100° C., preferably at the boiling point ofthe reaction mixture. The elimination of a benzyl or benzyloxycarbonylradical is, however, preferably effected by hydrogenolysis, for examplewith hydrogen in the presence of a catalyst such as palladium/charcoalin a solvent such as methanol, ethanol, ethyl acetate or glacial aceticacid, where appropriate with the addition of an acid such ashydrochloric acid, at temperatures between 0° and 50° C., but preferablyat room temperature, and under a hydrogen pressure of 1 to 7 bar, butpreferably 3 to 5 bar.

(b) Reduction of a Schiff's base, which is optionally formed in thereaction mixture, of the formula ##STR7## (in which R₁, R₂ and X are ashereinbefore defined, and

Y represents a group of the formula ##STR8## R₃ and A being ashereinbefore defined, R₅ " having the meanings mentioned hereinbeforefor R₅, but it being possible for an amino or alkylamino group containedin the radical R₅ to be protected by a protecting group, and

R₆ together with an .sup.α hydrogen atom of the adjacent carbon atom ofthe radical A representing a further bond), and, where appropriate,subsequent elimination of a protecting group which has been used.

Examples of suitable protecting groups for an amino or alkylamino groupare the acetyl, benzoyl, tert.butoxy-carbonyl, benzyloxycarbonyl,ethoxy-carbonyl or benzyl groups.

The reduction is carried out in a suitable solvent such as methanol,ethanol, diethyl ether, tetrahydrofuran, dioxane, ethyl acetate orethanol/ethyl acetate, with a metal hydride such as lithium aluminiumhydride, diborane, sodium cyanoborhydride or borane/dimethyl sulphide,but preferably with sodium borohydride, or with hydrogen in the presenceof a hydrogenation catalyst such as platinum, palladium/charcoal orRaney nickel, under a hydrogen pressure of 1 to 5 bar, or with hydrazinein the presence of a hydrogenation catalyst such as platinum,palladium/charcoal or Raney nickel, at temperatures between 0° and 50°C., preferably at room temperature. On reduction with a complex metalhydride such as lithium aluminium hydride, diborane orborane/dimethylsulphide it is possible for a carbonyl group present inthe radical R₅ " also to be reduced to a methylene group.

The subsequent elimination, where appropriate, of a protecting groupwhich has been used is preferably effected by hydrolysis in an aqueoussolvent, for example, in water, isopropanol/water, tetrahydrofuran/wateror dioxane/water, in the presence of an acid such as hydrochloric orsulphuric acid, or in the presence of an alkali metal base such assodium hydroxide or potassium hydroxide, at temperatures of between 0°and 100° C., preferably at the boiling point of the reaction mixture.However, the elimination of a benzyl or benzyloxycarbonyl radical ispreferably effected by hydrogenolysis, for example with hydrogen in thepresence of a catalyst such as palladium/charcoal in a solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, whereappropriate with the addition of an acid such as hydrochloric acid, attemperatures of between 0° and 50° C., but preferably at roomtemperature, and under a hydrogen pressure of 1 to 7 bar, but preferablyof 3 to 5 bar.

c) For the preparation of compounds of the general formula I in which R₃and R₄ are as hereinbefore defined, but in which R₃ and R₄ do notrepresent an ethylene group in which the methylene group adjacent to theN atom has been replaced by a carbonyl group:

reductive amination of a carbonyl compound of the general formula##STR9## (in which A is as hereinbefore defined,

R₅ " has the meanings mentioned hereinbefore for R₅ but it beingpossible for an amino or alkylamino group contained in the radical R₅ tobe protected by a protecting group, and

Z₃ together with a hydrogen atom of the adjacent carbon atom of theradical A representing an oxygen atom), with an amine of the generalformula ##STR10## (in which R₁, R₂ and X are as hereinbefore defined,

R₃ ' and R₄ ' have the meanings mentioned hereinbefore for R₃ and R₄,but R₃ and R₄ together not denoting an ethylene group in which themethylene group adjacent to the N atom has been replaced by a carbonylgroup) in the presence of a suitable reducing agent and, whereappropriate subsequent elimination of a protecting group which has beenused.

Examples of suitable protecting groups for an amino or alkylamino groupare the acetyl, benzoyl, tert.butoxy-carbonyl, benzyloxycarbonyl,ethoxy-carbonyl or benzyl groups.

The reductive amination is carried out in a suitable solvent such asmethanol, ethanol, tetrahydrofuran, dioxane or acetonitrile, in thepresence of a suitable reducing agent such as a suitable complex metalhydride, but preferably in the presence of sodium cyanoborohydride, at apH of 5 to 7, at temperatures of between 0° and 50° C., but preferablyat room temperature.

The subsequent elimination, where appropriate, of a protecting groupwhich has been used is preferably effected by hydrolysis in an aqueoussolvent, for example in water, isopropanol/water, tetrahydrofuran/wateror dioxane/water, in the presence of an acid such as hydrochloric acidor sulphuric acid, or in the presence of an alkali metal base such assodium hydroxide or potassium hydroxide, at temperatures of between 0°and 100° C., but preferably at the boiling point of the reactionmixture. However, the elimination of a benzyl or benzyloxy-carbonylradical is preferably carried out by hydrogenolysis, for example withhydrogen in the presence of a catalyst such as palladium/charcoal in asolvent such as methanol, ethanol, ethyl acetate or glacial acetic acid,where appropriate with the addition of an acid such as hydrochloricacid, at temperatures of between 0° and 50° C., but preferably at roomtemperature, and under a hydrogen pressure of 1 to 7 bar, but preferablyof 3 to 5 bar.

d) For the preparation of compounds of formula I in which R₃ representsa hydrogen atom:

reduction of a compound, which is optionally formed in the reactionmixture, of the general formula ##STR11## (in which A, X, R₁, R₂ and R₄are as hereinbefore defined, and R₅ " has the meanings mentionedhereinbefore for R₅ but it being possible for an amino or alkylaminogroup contained in the radical R₅ to be protected by a protectinggroup), and,

where appropriate, subsequent elimination of a protecting group whichhas been used.

Examples of suitable protecting groups for an amino or alkylamino groupare the acetyl, benzoyl, tert.butoxy-carbonyl, benzyloxycarbonyl,ethoxycarbonyl or benzyl groups.

The reduction is preferably carried out in a suitable solvent such asmethanol, ethanol, diethyl ether or tetrahydrofuran, in the presence ofa metal hydride such as sodium borohydride, lithium aluminium hydride,diborane, borane/dimethyl sulphide or sodium cyanoborohydride, butpreferably with sodium borohydride in methanol or ethanol, between 0 and40° C., but preferably at room temperature.

On reduction with a complex metal hydride such as lithium aluminumhydride, diborane or borane/dimethylsulphide, it is possible for acarbonyl group present in the radical R₅ " also to be reduced to amethylene group.

The subsequent elimination, where appropriate, of a protecting groupwhich has been used is preferably effected by hydrolysis in an aqueoussolvent, for example in water, isopropanol/water, tetrahydrofuran/wateror dioxane/water, in the presence of an acid such as hydrochloric acidor sulphuric acid, or in the presence of an alkali metal base such assodium hydroxide or potassium hydroxide, at temperatures between 0° and100° C., preferably at the boiling point of the reaction mixture.However, the elimination of a benzyl of benzyloxy carbonyl radical ispreferably effected by hydrogenolysis, for example with hydrogen in thepresence of a catalyst such as palladium/charcoal in a solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, whereappropriate with the addition of an acid such as hydrochloric acid, attemperatures of between 0° and 50° C., but preferably at roomtemperature, and under a hydrogen pressure of 1 to 7 bar, but preferablyof 3 to 5 bar.

e) For the preparation of compounds of formula I in which R₃ and R₄together represent an alkoxy-carbonylmethylene group:

reaction of a compound of the formula ##STR12## (in which A, X, R₁ andR₂ are as hereinbefore defined and

R₅ " has the meanings mentioned hereinbefore for R₅, but it beingpossible for an amino or alkylamino group contained in the radical R₅ tobe protected by a protecting group) with a compound of the generalformula

    O═CH--COOR.sub.7                                       (IX)

(in which

R₇ represents an alkyl group with 1 to 3 carbon atoms) and, whereappropriate, subsequent elimination of a protecting group which has beenused.

Examples of suitable protecting groups for an amino or alkylamino groupare the trityl, fluorenyl-methyloxy-carbonyl, benzyloxycarbonyl orbenzyl groups.

The reaction is expediently carried out in a solvent such as methylenechloride, chloroform, dioxane, benzene or toluene and, whereappropriate, in the presence of a water-abstracting agent such asp-toluenesulphonic acid or a molecular sieve, at temperatures between 0°C. and the boiling point of the solvent used, but preferably in benzeneor toluene under azeotropic distillation of the reaction mixture.

The subsequent elimination, where appropriate, of a protecting groupwhich has been used is preferably effected by hydrolysis under mild acidor basic conditions in an aqueous solvent, for example in water,isopropanol/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as acetic acid or trifluoroacetic acid, orunder non-aqueous conditions with tert.organic bases such astriethylamine or diazabicycloundecene (DBU), but preferably byhydrogenolysis, for example with hydrogen in the presence of a catalystsuch as palladium/charcoal in a solvent such as methanol, ethanol, ethylacetate or glacial acetic acid, under a hydrogen pressure of 1 to 7 bar,but preferably of 3 to 5 bar, at temperatures between 0° and 50° C., butpreferably at room temperature.

f) For the preparation of compounds of formula I in which R₅ representsan alkoxy group with 1 to 3 carbon atoms, an alkoxy group which has 1 to6 carbon atoms and which is substituted by a terminal carboxyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl ordialkylaminocarbonyl group, or an alkoxy group which has 2 to 7 carbonatoms and is substituted by a terminal hydroxy, alkoxy, amino,alkylamino, dialkylamino, pyrrolidino, piperidino or hexamethyleneiminogroup:

reaction of a compound of the formula ##STR13## (in which A, X and R₁ toR₃ are as hereinbefore defined and

R₄ " has the meanings mentioned hereinbefore for R₄ or represents areadily eliminatable protecting group for an amino group) with acompound of the formula

    Z.sub.4 --R.sub.8                                          (XI)

(in which

R₈ represents an alkyl group with 1 to 3 carbon atoms, an alkyl groupwhich has 1 to 6 carbons and is substituted by a terminal carboxyl,alkoxy-carbonyl, aminocarbonyl, alkylaminocarbonyl ordialkylaminocarbonyl group, or an alkoxy group which has 2 to 7 carbonatoms and is substituted by a terminal hydroxyl, alkoxy, amino,alkylamino, dialkylamino, pyrrolidino, piperidino or hexamethyleneiminogroup, and

Z₄ represents a nucleophilic leaving group such as a halogen atom or asulphonyloxy group, for example a chlorine, bromine or iodine atom, themethanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group,or

Z₄ together with a β-hydrogen atom of the radical R₈ represents anoxygen atom) and, where appropriate, subsequent elimination of aprotecting group which has been used.

Examples of suitable protecting groups, which can be readily eliminated,for the central nitrogen atom (R₄ ") are the acetyl, benzoyl,tert.butoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl or benzyl groups.

The reaction is expediently carried out in a solvent such as diethylether, tetrahydrofuran, dioxane, methanol, ethanol or dimethylformamide,and preferably in the presence of an acid-binding agent such as sodiumhydroxide or potassium tert.butylate; but preferably in the presence ofpotassium carbonate or sodium hydride, or pyridine, it also beingpossible for an organic base such as pyridine to serve as solvent, orfor the preparation of 2-hydroxyethoxy compounds of the general formulaI with ethylene oxide, at temperatures of between 0° and 100° C., butpreferably at temperatures of between 20° and 80° C.

The subsequent elimination, where appropriate, of a protecting groupwhich has been used is preferably effected by hydrolysis in an aqueoussolvent, for example in water, isopropanol/water, tetrahydrofuran/wateror dioxane/water, in the presence of an acid such as hydrochloric acidor sulphuric acid, or in the presence of an alkali metal base such assodium hydroxide or potassium hydroxide, at temperatures of between 0°and 100° C., preferably at the boiling point of the reaction mixture.However, the elimination of a benzyl or benzyloxycarbonyl radical ispreferably effected by hydrogenolysis, for example with hydrogen in thepresence of a catalyst such as palladium/charcoal in a solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, whereappropriate with the addition of an acid such as hydrochloric acid, attemperatures of between 0° and 50° C., but preferably at roomtemperature, and under a hydrogen pressure of 1 to 7 bar, but preferablyof 3 to 5 bar.

g) For the preparation of compounds of the general formula I in which R₃represents a hydrogen atom:

reduction of a compound of the general formula ##STR14## in which A, X,R₁, R₂ and R₄ are as hereinbefore defined, and

R₃ " denotes a hydrogen atom or an alkyl group.

The reduction is carried out in a suitable solvent such as diethyl etheror tetrahydrofuran, with a reducing agent such as a metal hydride, forexample with lithium aluminum hydride, diborane or diborane/dimethylsulphide, but preferably with sodium borohydride in the presence ofglacial acetic acid or trifluoroacetic acid, at temperatures of between0° and 50° C., but preferably at temperatures of between 10° and 25° C.During the reduction a carbonyl group which is optionally present in theradicals R₄ and R₅ can at the same time also be reduced to a methylenegroup. Furthermore, a cyano group present in the radical R₄ can also bereduced to an aminomethylene group.

h) For the preparation of compounds of formula I in which R₅ representsor contains an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, ordialkylaminocarbonyl group:

reaction of a compound of the formula ##STR15## (in which R₁ to R₄, Aand X are as hereinbefore defined, and

R₅ "' represents a carboxyl group or an alkoxy group which has 1 to 6carbon atoms and is substituted by a terminal carboxyl group) or of itsreactive derivatives such as, for example, its esters, with a compoundof the formula

    H--R.sub.9                                                 (XIV)

in which

R₉ represents an alkoxy, amino, alkylamino or dialkylamino group, itbeing possible, however, for each alkyl or alkoxy moiety to contain 1 to3 carbon atoms.

The esterification or amidation is expediently carried out in a solventsuch as methylene chloride, chloroform, carbon tetrachloride, ether,tetrahydrofuran, dioxane, benzene, toluene, acetonitrile ordimethylformamide, but particularly advantageously in an excess of acompound of formula XIV which is used, for example in methanol, ethanol,n-propanol, isopropanol, ammonia, methylamine, ethylamine, dimethylamineor diethylamine, where appropriate in the presence of an acid activatingagent or of a water-abstracting agent, for example in the presence ofethyl chloroformate, thionyl chloride, phosphorus trichloride,phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,N,N'-dicyclohexyl-carbodiimide/N-hydroxysuccinimide,N,N'-carbonyl-diimidazole or N,N'-thionyldiimidazole ortriphenyl-phosphine/carbon tetrachloride, or of an agent activating theamino group, for example phosphorus trichloride and, where appropriate,in the presence of an inorganic base such as sodium carbonate or atertiary organic base such as triethylamine or pyridine, which can atthe same time serve as solvents, at temperatures between -25° C. and250° C., but preferably at temperatures of -10° C. and the boiling pointof the solvent used.

i) For the preparation of compounds of formula I in which R₄ representsan alkyl group which is optionally substituted by a phenyl, carboxyl,alkoxycarbonyl or cyano group or, in the 2- or 3-position, by a hydroxylgroup, or represents an alkenyl group:

reaction of a compound of the formula ##STR16## (in which A, X and R₁ toR₃ are as hereinbefore defined, and

R₅ "" has the meanings hereinbefore mentioned for R₅ but it beingpossible, where necessary, for an amino or alkylamino group contained inthe radical R₅ to be protected by a protecting group) with a compound ofthe general formula

    Z.sub.5 --R.sub.4 "'                                       (XVI)

(in which

R₄ "' has, with the exception of the hydrogen atom, the meaningsmentioned hereinbefore for R₄, and

Z₅ denotes a nucleophilic leaving group such as a halogen atom or asulphonyloxy group, for example a chlorine, bromine or iodine atom, themethanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group,or

Z₅ together with an α or β hydrogen atom of the alkyl radical R₄ "'denotes an oxygen atom) and, where appropriate, subsequent eliminationof a protecting group which has been used.

The alkylation is carried out in a suitable solvent such as methanol,ethanol, diethyl ether, acetone, methylene chloride, tetrahydrofuran,dioxane, dimethylformamide or dimethyl sulphoxide, where appropriate inthe presence of a base such as sodium carbonate, potassiumtert.butylate, triethylamine or pyridine, it also being possible,however, for the two latter also at the same time to serve as solvents,with a suitable alkylating agent such as methyl iodide, dimethylsulphate, ethyl bromide, diethyl sulphate, benzyl chloride, n-propylbromide, isopropyl bromide, allyl bromide, ethylene oxide,2-hydroxy-ethyl bromide, 2-cyano-ethyl bromide or formaldehyde/formicacid, or in the presence of sodium cyanoborohydride if an appropriatecarbonyl compound is used, at temperatures between 0° and 100° C.

The subsequent elimination, where appropriate, of a protecting groupwhich has been used is preferably carried out by hydrolysis in anaqueous solvent, for example in water, isopropanol/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas hydrochloric acid or sulphuric acid, or in the presence of an alkalimetal base such as sodium hydroxide or potassium hydroxide, attemperatures between 0° and 100° C., preferably at the boiling point ofthe reaction mixture. The elimination of a benzyl or benzyloxycarbonylradical is, however, preferably effected by hydrogenolysis, for examplewith hydrogen in the presence of a catalyst such as palladium/charcoalin a solvent such as methanol, ethanol, ethyl acetate or glacial aceticacid, where appropriate with the addition of an acid such ashydrochloric acid, at temperatures between 0° and 50° C., but preferablyat room temperature, and under a hydrogen pressure of 1 to 7 bar, butpreferably 3 to 5 bar.

k) For the preparation of compounds of formula I in which R₃ and R₄together represent an ethylene group:

reduction of a compound, which is optionally formed in the reactionmixture, of the formula ##STR17## in which A, X, R₁, R₂ and R₅ are ashereinbefore defined, or of its cyclic hemiacetal.

The reaction is preferably carried out in a solvent such as methylenechloride, chloroform or trifluoroacetic acid with a suitable hydridesuch as a complex metal hydride, for example with sodium borohydride,with catalytically activated hydrogen, for example with hydrogen in thepresence of platinum, or with a trialkylsilane, for example withtriethylsilane, where appropriate in the presence of an acid such asboron trifluoride, for example in the presence of boron trifluorideetherate, at temperatures between 0° and 60° C., but preferably intrifluoroacetic acid as solvent and at room temperature.

l) For the preparation of compounds of formula I in which R₃ and R₄together denote an ethylene group in which the methylene group adjacentto the N or O atom has been replaced by a carbonyl group:

reaction of a compound of the formula ##STR18## in which A, X, R₁, R₂and R₅ are as hereinbefore defined, with a haloacetyl halide orhaloacetic acid.

The reaction is expediently carried out in a solvent such as methylenechloride, tetrahydrofuran, dioxane, benzene or toluene, or in an excessof the acylating agent which is used, where appropriate in the presenceof an acid-binding agent such as potassium carbonate, an alkali metalhydride such as sodium hydride or in the presence of a tertiary organicbase such as triethylamine or pyridine, it also being possible for thetwo latter at the same time to serve as solvents, at temperaturesbetween 0° and 100° C., but preferably at temperatures of between roomtemperature and the boiling point of the reaction mixture. When ahaloacetic acid ester in the presence of potassium carbonate is used forthe reaction, a corresponding lactone is preferentially obtained.

m) For the preparation of compounds of formula I in which R₃ and R₄together denote an ethylene group:

reduction of a compound of the formula ##STR19## in which A, X, R₁, R₂and R₅ are as hereinbefore defined,

The reduction is carried out in a suitable solvent such as diethyl etheror tetrahydrofuran with a reducing agent such as a metal hydride, forexample with lithium aluminium hydride or sodium borohydride in thepresence of glacial acetic acid or trifluoroacetic acid, but preferablywith phosphorus oxychloride/sodium borohydride, diborane ordiborane/dimethyl sulphide, at temperatures of between 0° and 50° C.,but preferably at temperatures of between 10° and 25° C. During thereduction a carbonyl group which is optionally present in the radical R₅can also at the same time be reduced to a methylene group.

n) For the preparation of compounds of formula I in which R₃ and R₄together represent an ethylene group in which the methylene groupadjacent to the O atom has been replaced by a carbonyl group:

cyclisation of a compound, which is optionally formed in the reactionmixture, of the formula ##STR20## in which A, X, R₁, R₂ and R₅ are ashereinbefore defined, or of its reactive derivative such as its estersor halides.

The cyclisation is carried out in a suitable solvent such as methylenechloride, chloroform, benzene, toluene, tetrahydrofuran, acetone, methylethyl ketone or dioxane, where appropriate in the presence of awater-abstracting agent such as thionyl chloride, phosphorustrichloride, N,N'-dicyclohexylcarbodiimide, N,N'-carbonyl diimidazole orN,N'-thionyldiimidazole, at temperatures of between 0° and 100° C., butpreferably at the boiling point of the reaction mixture.

o) For the preparation of compounds of formula I in which R₁ representsa hydrogen or halogen atom, a trifluoromethyl or alkyl group, and R₃represents a hydrogen atom:

reaction of a compound of the formula ##STR21## (in which X and R₂ areas hereinbefore defined, and

R₁ ' represents a hydrogen or halogen atom, a trifluoromethyl or alkylgroup) with an amine of the formula ##STR22## in which A, R₄ and R₅ areas hereinbefore defined,

The reaction is carried out in a suitable solvent, for example in apolar solvent such as ethanol or isopropanol or in an aprotic solventsuch as dimethylformamide or dimethyl sulphoxide, at temperaturesbetween 0° and 150° C., but preferably at temperatures between 50° and100° C.

When there is obtained, according to the invention, a compound offormula I in which R₅ represents or contains an alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group and/orR₁ represents an amino group which is substituted by an alkanoyl orbenzoyl group, this can, by hydrolysis, be converted into acorresponding compound of formula I in which R₅ represents or contains acarboxyl group and/or R₁ represents an amino group, or

a compound of formula I in which R₅ represents an alkoxy group which issubstituted by a carboxyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl or dialkylaminocarbonyl group, this can, by reductionwith a suitable metal hydride, be converted into a compound of formula Iin which the above-mentioned substituted alkoxy radical contains amethylene group in place of the carbonyl group, or

a compound of formula I in which R₃ represents an alkyl group and/or R₅represents one of the alkoxy groups mentioned hereinbefore, this can, byether cleavage, be converted into a corresponding compound of formula Iin which R₃ represents a hydrogen atom and/or R₅ represents a hydroxylgroup or an alkoxy group which is substituted by a hydroxyl group.

The subsequent hydrolysis is carried out either in the presence of anacid such as hydrochloric acid, sulphuric acid, phosphoric acid ortrichloroacetic acid, or in the presence of a base such as sodiumhydroxide or potassium hydroxide, in a suitable solvent such as water,methanol, ethanol, ethanol/water, water/isopropanol or water/dioxane, attemperatures of -10° C. and 120° C., for example at temperatures betweenroom temperature and the boiling point of the reaction mixture.

The subsequent reduction is carried out in a suitable solvent such asdiethyl ether or tetrahydrofuran with a suitable metal hydride, forexample with lithium aluminium hydride, diborane or diborane/dimethylsulphide, but preferably with sodium borohydride in the presence ofglacial acetic acid or trifluoroacetic acid, at temperatures of between0° and 50° C., but preferably at temperatures between 10° and 25° C.

The subsequent ether cleavage is carried out in the presence of an acidsuch as hydrogen chloride, hydrogen bromide, sulphuric acid or borontribromide in a suitable solvent such as methanol, ethanol,water/isopropanol, methylene chloride, chloroform or carbontetrachloride, at temperatures between -30° C. and the boiling point ofthe reaction mixture.

It is possible during the subsequent hydrolysis, reduction or ethercleavage for compounds of formula I in which R₃ and R₄ together denotean ethylene group in which the methylene group adjacent to the O atomhas been replaced by a carbonyl group to be simultaneously cleaved.

As already mentioned the new compounds can exist in the form of theirenantiomers, enantiomer mixtures or racemates, or, where they contain atleast two asymmetric carbon atoms, in the form of their diastereomers ordiastereomer mixtures.

Thus, the compounds of formula I which have been obtained and whichcontain only one optically active centre can be separated into theiroptical antipodes by methods known per se (see Allinger N. L. and ElielE. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971)as, for example by recrystallisation from an optically active solvent orby reaction with an optically active substance, in particular acids,which forms salts with the racemic compound, and separation of themixture of salts obtained in this manner, for example on the basis ofdifferent solubilities, into the diastereomeric salts, from which thefree antipodes can be liberated by the action of suitable agents.Examples of particularly useful optically active acids are the D-andL-forms of tartaric acid, di-O-toluyl tartaric acid, malic acid,mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid orquinic acid.

Furthermore, the compounds of formula I which have been obtained andhave at least 2 asymmetric carbon atoms can be separated into theirdiastereomers on the basis of their physical chemical differences bymethods known per se, for example by chromatography and/or fractionalcrystallisation. A pair of enantiomers which has been obtained in thisway can be separated into its optical isomers as described above. If,for example, a compound of formula I contains two optically activecarbon atoms then the corresponding (R R', S S') and (R S', S R') formsare obtained.

The compounds used as starting materials, which, of course, can also beused in their optically pure forms, are obtained by processes known fromthe literature (see "Thiazole and its Derivatives" in HeterocyclicCompounds, Vol. 34, and Advances in Heterocyclic Chemistry, Vol. 17,page 100 (1974)) or are themselves known from the literature. Some ofthem are present only in the reaction mixture, and thus some of themcannot be isolated.

The compounds which are used as starting materials, of formula II inwhich Z₁ represents a nucleophilic leaving group, are obtained byreduction of a corresponding acetyl compound, for example with a complexmetal hydride and, where appropriate, subsequent alkylation.

A compound of formula IV which need not be isolated is obtained byreaction of a compound of the general formula ##STR23## with a carbonylcompound of the formula ##STR24## or by reaction of an amine of theformula ##STR25## with a glyoxal of the formula ##STR26## (in which R₁to R₃, R₅, A and X are as hereinbefore defined

R₅ " has the meanings mentioned hereinbefore for R₅ whilst an amino oralkylamino group contained in the radical R₅ may be protected by aprotecting group, and

Z₃ together with one hydrogen atom on the adjacent carbon atom of theradical A represents an oxygen atom) in the presence of sodiumcyanoborohydride in a suitable solvent such as methylene chloride,chloroform, dioxan, benzene or toluene and, where appropriate, in thepresence of a water-abstracting agent such as p-toluenesulphonic acid ora molecular sieve, at temperatures between 0° C. and the boiling pointof the solvent used, but preferably in benzene or toluene by azeotropicdistillation of the reaction mixture.

A compound which is necessary for the preparation of these startingcompounds having the formula ##STR27## (in which R₁, R₂ and X are ashereinbefore defined is obtained by bromination of the correspondingacetyl compounds in glacial acetic acid or hydrogen bromide/glacialacetic acid at temperatures between 20° and 100° C., or, where R₂ in the5-position represents a hydrogen atom, and X represents a sulphur atom,by ring closure of the corresponding thioamides with dibromodiacetyl ina solvent such as diethyl ether or acetonitrile. Furthermore, forexample the above-mentioned acetyl compounds are obtained, when R₂ inthe 4-position represents a methyl group and X represents a sulphuratom, by reaction of a corresponding thioamide with 3-chloroacetoacetonein water, ethanol, water/ethanol or in a melt (see Z. Chem. 9, 187(1969)) or, when R₂ in the 5-position represents a methyl group and Xrepresent an oxygen or sulphur atom, by reaction of a correspondingacylaminoacetoacetone with dehydrating agents (see Chem. Ber. 84, 96(1951) and Chem. Ber. 93, 1998 (1960)) or with phosphorus pentasulphideor with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulphide.

An amino-ketone of formula VII is obtained in the reaction mixture byreaction of corresponding bromoacetyl derivative with an appropriateamine or with urotropine, followed by hydrolysis.

The compounds which are used as starting materials having the formulaeVIII, X, XIII, XV and XX are expediently obtained by alkylation of anappropriate amine.

The compounds which are used as starting materials and have the formulaXII are obtained by acylation of an appropriate amine.

A compound which is used as starting material and has the formula XXI isobtained for example by reaction of an appropriate bromohydrin withaqueous potassium hydroxide solution or by reaction of an appropriatealdehyde with dimethylsulphonium methylide at 0° C. in dimethylsulphoxide/tetrahydrofuran.

A corresponding glyoxal is obtained, for example, by reaction of anappropriate bromoacetyl compound of formula XXVI with dimethylsulphoxide at room temperature.

Furthermore, the compounds of formula I which have been obtained can beconverted into their acid addition salts, in particular forpharmaceutical use into their physiologically acceptable salts, withinorganic or organic acids. Examples of suitable acids for this purposeare hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoricacid, fumaric acid, succinic acid, lactic acid, citric acid, tartaricacid or maleic acid.

As already mentioned above, the new compounds of formula I in which R₃and R₄ together denote an ethylene group in which the methylene groupattached to the N atom is replaced by a carbonyl group (see Formula XIX)represent valuable intermediates for the preparation of the morpholinesof formula I.

The other new compounds of formula I (excepting the lactams), theirenantiomers, enantiomer mixtures or racemates, or, where they contain atleast 2 asymmetric carbon atoms, their diastereomers or diastereomermixtures, and their acid addition salts, in particular forpharmaceutical use their physiologically acceptable acid addition salts,have valuable pharmacological properties, besides an inhibition effecton platelet aggregation, in particular an action on the metabolism,preferentially a blood sugar lowering and body fat reducing action. Thepresent invention thus provides pharmaceutical compositions comprisingan effective blood sugar lowering amount, or an effective antiadiposeamount, of a compound of Formula I, other than the lactams thereof, incombination with a nontoxic, pharmaceutically acceptable carrier.

In addition, some of the above-mentioned compounds also have an anabolicaction as well as causing a reduction in the levels of atherogenicβ-lipoproteins PG,43 VLDL and LDL. In this connection, where R₁represents a trifluoromethyl group, the diastereomer which has proved tobe particularly preferred is the one whose proton in the 5-position ofthe thiazole ring is located at lower field in the CDCl₃ /CD₃ OD-NMRspectrum in the morpholine series and in the CDCl₃ -NMR spectrum in theethanolamine series.

The following compounds, for example, have been investigated for theirbiological properties, as follows:

A=N-[2-(4-Carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

B=N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

C=N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

D=N-[2-(4-Methylaminocarbonylmethoxphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

E=N-[2-(4-Carboxphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

F=N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine,

G=Methyl3-[2-(4-carbomethoxyphenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate (diastereomer pairs A and B),

H=Methyl3-[2-(4-carbomethoxyphenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate (diastereomer pairs C and D),

I=Methyl3-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate (diastereomer pairs A and B).

J=Methyl3-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate (diastereomer pairs C and D),

K=N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-methyl-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine,

L=N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine,

M=N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine,

N=N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(thiazol-4-yl)ethanamine,

O=N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2(2-trifluoromethyl-thiazol-4-yl)morpholine,

P=N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanamine,

Q=N-[2-(4-(Hydroxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamineand

R=Methyl3-[2-(4-(2-carbomethoxy-1-methylethenyl)phenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate

1. Antidiabetic action:

The antidiabetic action of the compounds according to the invention canbe measured as a blood sugar lowering action in experimental animals.For this purpose, the substances for investigation were suspended in1.5% methyl cellulose and administered by gavage to female mice of ourown breed. 30 minutes later 1 g of glucose per kg of body weight wasdissolved in water and administered subcutaneously. A further 30 minuteslater blood was taken from the retroorbital venus plexus. Glucose in theserum was determined by the hexokinase method using an analyticalphotometer.

The Table which follows lists the lowerings of blood sugar, as a % of aparallel control group, observed in this design of experiment.Statistical analysis employed Student's t-test with p=0.05 assignificance limit.

    ______________________________________                                                % change from figure for the control group                                    Dose [mg/kg]                                                          Compound  0.3      1      3       10   30                                     ______________________________________                                        A                  -40                 -63                                    B                  -64            -73                                         C                         -68          -76                                    D                  -65                 -68                                    E                         -57          -70                                    F                         -61     -64                                         G                         -56                                                 H                         -59                                                 I                  -68            -72                                         J         -36                     -60                                         K                  -42                 -60                                    L                         -61                                                 M                  -32            -58                                         N                         -23                                                 O                         -60                                                 P         -52                                                                 Q                  -70                                                        R                         -56                                                 ______________________________________                                    

2. Antiadipose action:

The antiadipose action of the compounds according to the invention wasdemonstrated using two experimental procedures:

a) In the first experimental procedure, the increase in lipolysis wasmeasured by the rise in serum glycerol. The experimental procedure isidentical to the experimental procedure described above for testing theblood sugar lowering action. Glycerol was determined in a combinedenzymatic/colorimetric assay using an analytical photometer. The resultsare listed in the Table which follows, as a % of a parallel control.

    ______________________________________                                                % change from figure for the control group                                    Dose [mg/kg]                                                          Compound  0.3      1      3       10   30                                     ______________________________________                                        A                          88                                                 B                  312            326                                         C                         504          732                                    D                  433                 439                                    E                         226          305                                    F                         413     430                                         G                         209                                                 H                         168                                                 I                  204            228                                         J         260                     391                                         K                  283                 416                                    L                         220                                                 M                  307            453                                         N                         (8)                                                 O                         336                                                 P         217                                                                 Q                  221                                                        R                         758                                                 ______________________________________                                         ( ) = not significant (p > 0.05)                                         

b) In the second experimental procedure to detect an antiadipose actionof the compounds according to the invention, the reduction in adiposetissue was measured by monitoring the ovarian adipose tissue. For thispurpose, the compounds were administered by gavage in a suspension of1.5% methyl cellulose once a day to mice. On the fifth day, the ovarianadipose tissue was dissected out and weighed. The Table which followsshows the results as a % of a parallel control group.

    ______________________________________                                                  % change from figure for the control group                          Compound  Dose: 10 [mg/kg]                                                    ______________________________________                                        A         -36                                                                 B         -60                                                                 C         -35                                                                 D         -30                                                                 F         -47                                                                 G         -33                                                                 H         -20                                                                 I         -28                                                                 J         -11                                                                 K         -12                                                                 L         -53                                                                 M         -48                                                                 ______________________________________                                    

3. Cardiac side effects:

It was possible to rule out the occurrence of undesired side effects onthe heart by the compounds according to the invention in the dose rangehaving metabolic activity and intended for therapy. The demonstrationentailed measurement of the heart rate of mice during the testing of theblood sugar lowering action (see above). One hour after the oraladministration of the compounds the heart rate was determined by aECG-triggered tachograph. The Table which follows shows the change inthe heart rate as a percentage of the control group.

    ______________________________________                                                     % change from figure                                                          for the control group                                                         Dosage [mg/kg]                                                   Compound       0.3          1          3                                      ______________________________________                                        A                            (21)                                             B                           (0)                                               C                                      (11)                                   D                           17.sup.                                           E                                      17.sup.                                F                                      (9)                                    I                           (3)                                               J              (0)                                                            K                           (-4)                                              M                           (-1)                                              O                                      (7)                                    ______________________________________                                         ( ) = not significant (p > 0.05)                                         

Furthermore, in the investigations which are described above, no toxicside effects were observed for the substances according to the inventionat the doses administered. Hence they are well tolerated.

Thus, on the basis of their pharmacological properties, the newcompounds of formula I (other than the lactams) and their opticalisomers, diastereomers and physiologically acceptable acid additionsalts with inorganic or organic acids, are suitable for the treatmentboth of diabetes mellitus and of obesity, and thus in particular for thetreatment of the obese diabetic. In addition, said compounds may be usedfor the prophylaxis and the treatment of atherosclerotic changes inblood vessels which occur particularly frequently in the case of thosesuffering from diabetes and/or obesity. In this connection, it ispossible entirely to suit the requisite dose to themetabolic/physiological requirements of the individual patient, sincethe compounds have no cardiovascular action over a wide dose range.Thus, the daily dose for adults is between 1 and 3000 mg, but preferably1 to 1000 mg, distributed over 1 to 4 doses per day. For this purpose,the above-mentioned compounds, with or without other active substances,can be incorporated into the customary pharmaceutical unit dosage formssuch as powders, tablets, coated tablets, capsules, suppositories orsuspensions.

Furthermore, the above-mentioned compounds can be used for the treatmentof obese animals such as dogs, and, as a consequence of their actionreducing body fat (lypolysis), can be used to reduce undesired fattydeposits in fatstock rearing, that is to say to improve the quality ofmeat from fatstock such as pigs, cattle, sheep and poultry. Theadministration of the above-mentioned compounds to the animals can beaffected orally or non-orally, for example as a feed supplement or byinjection or by implanted minipumps. The daily dose for this purpose isbetween 0.01 and 100 mg/kg, but preferably between 0.1 and 10 mg/kg ofbody weight.

The present invention thus provides a method of treating an individualafflicted with diabetes mellitus which comprises administering to saidindividual an effective blood sugar lowering amount of a compound ofFormula I (other than the lactams). The invention also provides a methodof treating an individual afflicted with obesity, or an animal, whichcomprises administering to same an effective antiadipose amount of saidcompound.

The Examples which follow are intended to illustrate the invention indetail:

Example A

2-Trifluoromethyl-4-bromoacetylthiazole

9.2 g (0.071 mol) of Trifluoromethylthioacetamide, dissolved in 200 mlof acetonitrile, are added dropwise in 2.5 hours to a boiling solutionof 17.4 g (0.071 mol) of dibromodiacetyl in 200 ml of acetonitrile. Thesolvent is removed by distillation, and the remaining product isextracted with cyclohexane. The extract is concentrated, and theremaining oily residue is purified on a silica gel column usingtoluene/cyclohexane as eluant.

Yield: 8.2 g (42.7% of theory),

M.p.: 36°-37° C.

Example B

2,4-Dimethyl-5-acetyl-thiazole

A mixture of 34 g (0.25 mol) of 3-chloroacetoacetone and 19 g (0.25 mol)of thioacetamide is slowly heated, with stirring. An exothermic reactionstarts at about 60° C. The heating bath is removed, and the product isthen stirred for 1 hour and allowed to cool during this. Theprecipitated hydrobromide is triturated with petroleum ether/ethanol=5/1 and filtered off with suction. For the conversion into the freebase, the salt is dissolved in water and made alkaline with sodiumbicarbonate. The mixture is then extracted several times with methylenechloride, the organic phase is dried over sodium sulphate andconcentrated, and the residue is purified on a silica gel column usingtoluene as eluant.

Yield: 19.7 g (51% of theory)

¹ H-NMR spectrum (CDCl₃): δ=2.50 ppm (s, CH₃)

Example C

2,4-Dimethyl-5-bromoacetyl-thiazole

A solution of 20.8 g (0.13 mol) of bromine in 50 ml of glacial aceticacid is slowly added dropwise to a solution of 20.2 g (0.13 mol) of2,4-dimethyl-5-acetyl-thiazole in glacial acetic acid, heated to reflux.After 1 hour, the mixture is evaporated to dryness, the residue isdissolved in water, and the solution is neutralised with sodiumcarbonate solution. The mixture is then extracted several times withmethylene chloride, and the organic phase is dried and concentrated. Theoil which was obtained in this way was used for further reactionswithout further purification.

Yield: 24 g (79% of theory).

Example D

2-Phenyl-4-formyl-thiazole-cyanohydrin

16.4 g (0.0607 mol) of 2-phenyl-4-formyl-thiazol-hydrobromide in 230 mlof water and 150 ml of dioxan are heated to 30° C. on a steam bath,during which about 80-90% of the substance dissolves. The mixture isthen cooled to 20° C. in an ice bath and, while stirring vigorously, 22g (0.162 mol) of potassium dihydrogen phosphate are added in portions.Then 6.1 g (0.124 mol) of sodium cyanide is introduced in portions, andthe mixture is stirred at room temperature for 1.5 hours. Theprecipitated product is extracted with ether, the organic phase is driedover sodium sulphate and concentrated, and the residue is dried invacuo.

Yield: 13 g (100% of theory),

M.p.: 140°-141° C.

    ______________________________________                                        Calculated:                                                                            C      62.20  H    3.72 N    12.95                                                                              S    14.82                         Found:          62.35       3.91      12.89     14.93                         ______________________________________                                    

Example E

2-(2-Trifluoromethyl-thiazol-4-yl)glyoxal

3 g (0.011 mol) of 2-Trifluoromethyl-4-bromoacetyl-thiazole aredissolved in 30 ml of dimethyl sulphoxide and the solution is maintainedat room temperature for 70 hours. It is then poured onto 100 g of ice,and the mixture is extracted several times with ether, the organic phaseis dried over sodium sulphate and concentrated, and the residue ispurified on a silica gel column using toluene/ethyl acetate =7/3 aseluant.

Yield: 1.3 g (56% of theory).

Example F

2-Trifluoromethyl-5-methyl-4-bromoacetyl-oxazole

a) 3-Trifluoroacetamino-acetoacetone

10 g (0.0662 mol) of 3-Amino-acetoacetone hydrochloride are cautiouslymixed with 56 g (0.266 mol) of trifluoroacetic anhydride. The reactionmixture foams vigorously and then a clear solution forms. The mixture isboiled under reflux for 30 minutes, and then the solvent is removed, theresidue is taken up in 500 ml of ether, and the solution is shaken threetimes with 100 ml of saturated sodium bicarbonate solution each time.The ether phase is dried over sodium sulphate and concentrated.

Yield: 12 g (86% of theory),

M.p.: 44°-46° C.

    ______________________________________                                        Calculated:                                                                              C     39.81    H   3.81   N   6.63                                 Found:           39.80        3.67       6.87                                 ______________________________________                                    

b) 2-Trifluoromethyl-5-methyl-4-acetyl-oxazole

5 g (0.0237 mol) of 3-Trifluoroacetaminoacetoacetone are heated with 5ml of trifluoroacetic anhydride on a steam bath for 4 hours. During thisthe solution changes colour and the trifluoroacetic anhydride almostcompletely evaporates. The residue is dissolved in 100 ml of chloroform,and the solution is shaken three times with 50 ml of saturated sodiumbicarbonate solution each time. The chloroform phase is dried oversodium sulphate and evaporated.

Yield: 3.2 g (70% of theory),

¹ H-NMR spectrum (CDCl₃): δ=2.52 ppm (s, CH₃); 2.65 ppm (s, CH₃).

c) 2-Trifluoromethyl-5-methyl-4-bromoacetyl-oxazole

5.8 g (0.02 mol) of 2-Trifluoromethyl-5-methyl-4-acetyl-oxazole aredissolved in 30 ml of glacial acetic acid, and 3 ml of a 33% strengthsolution of hydrogen bromide in glacial acetic acid are added. Themixture is heated to 80° C. and, over the course of 1 hour, a solutionof 3.2 g (0.02 mol) of bromine in 10 ml of glacial acetic acid is added.After a further 30 minutes the glacial acetic acid is removed. Theresidue which remains is a dark oil which is reacted further as thecrude product.

Yield: 4.4 g (81% of theory),

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=2.72 ppm (s, CH₃) 4.52 ppm (s, CH₂)

Example G

2,5-Dimethyl-4-bromoacetyl-oxazole

2.8 g (0.02 mol) of 2,5-Dimethyl-4-acetyl-oxazole are dissolved in 30 mlof glacial acetic acid, and 3 ml of a 35% strength solution of hydrogenbromide in glacial acetic acid are added. The mixture is heated to 100°C. and, over the course of 1 hour, a solution of 3.2 g (0.02 mol) ofbromine in 10 ml of glacial acetic acid is added. After a further 2hours the solvent is removed, and the residue is triturated with 50 mlof ether and filtered off with suction.

Yield: 4.4 g (74% of theory),

M.p.: 175°-176° C.

    ______________________________________                                        Calculated:                                                                            C      28.12  H    3.03 N    4.68 Br   53.45                         Found           28.29       2.93      4.78      53.37                         ______________________________________                                    

Example H

2-Methyl-4-formyl-thiazole-cyanohydrin

Prepared analogously to Example D by reaction of2-methyl-4-formyl-thiazole with sodium cyanide and potassium dihydrogenphosphate in dimethylformamide/water =1/1. After extraction with ethylacetate and drying of the extract with sodium sulphate, purification iscarried out on a silica gel column using toluene/ethyl acetate =8/2 aseluant.

Yield: 41% of theory,

M.p.: 116°-117° C.

¹ H-NMR spectra (DMSO/CD₃ OD): δ=7.580 ppm (s, 1H)

Example I

4-Formyl-thiazole-cyanohydrin

Prepared analogously to Example D by reaction of4-formyl-thiazole-hydrobromide with sodium cyanide and potassiumdihydrogen phosphate in water. The precipitate which has separated outis filtered off with suction and washed with water. After drying in avacuum dessicator, almost colourless crystals are obtained and arereacted without further purification.

Yield: 53% of theory,

M.p.: 113°-115° C.

Example K

2-Trifluoromethyl-5-methyl-4-bromoacetyl-thiazole

a) 2-Trifluoromethyl-5-methyl-4-acetyl-thiazole

5.8 g (0.0275 mol) of 3-Trifluoroacetaminoacetoacetone are heated at100° C. with 6.4 g (0.0158 mol) of2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulphide in35 ml of absolute toluene, with stirring and under nitrogen, for 10hours. The resulting clear solution is concentrated, and the residue ispurified on a silica gel column using methylene chloride as eluant.

Yield: 3.1 g (54% of theory),

    ______________________________________                                        Calculated:                                                                            C      40.19  H    2.88 N    6.69 S    15.32                         Found:          40.45       2.69      6.87      15.33                         ______________________________________                                    

b) 2-Trifluoromethyl-5-methyl-4-bromoacetyl-thiazole

3 g (0.0144 mol) of 2-Trifluoromethyl-5-methyl-4-acetyl-thiazole aredissolved in 30 ml of glacial acetic acid, and 2.1 ml of a 33% strengthsolution of hydrogen bromide in glacial acetic acid are added. Themixture is heated to 80° C. and, over the course of 30 minutes, asolution of 2.3 g (0.0144 mol) of bromine in 15 ml of glacial aceticacid is added. After a further 20 minutes, the glacial acetic acid isremoved. The residue which remains is a dark oil which is reactedfurther as the crude product.

Yield: 3.8 g (92% of theory),

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=2.90 (s,CH₃); 4.70 (s,CH₂).

Example L

2-Hydroxy-2-(2-propyl-thiazol-4-yl)ethanamine

Prepared analogously to Example P by reduction of4-(α-cyano-α-hydroxy-methyl)-2-propyl-thiazole (melting point: 68°-70°C.) with sodium borohydride in a mixture of tetrahydrofuran andtrifluoroacetic acid. For working up, water is added while cooling, andthe mixture is stirred until the precipitate which has formed hasdissolved, then the solution is acidified with concentrated hydrochloricacid and heated at 20° C. for 30 minutes and at 100° C. for 60 minutes.After cooling and addition of water, the organic phase is separated offand discarded. The acidic aqueous phase is extracted once more withethyl acetate, which is discarded. Then, while cooling in ice, thesolution is made strongly alkaline with 6N sodium hydroxide solution.Extraction with chloroform several times and drying, filtration andevaporation of the chloroform solution in vacuo are followed bycrystallisation from ether of the residue from evaporation.

Yield: 75% of theory,

M.p.: 73°-75° C.

Example M

2-Hydroxy-2-(2-isopropyl-thiazol-4-yl)ethanamine

Prepared analogously to Example L by reduction of4-(α-cyano-α-hydroxymethyl)-2-isopropyl-thiazole (melting point: 56°-58°C.) with sodium borohydride in a mixture of tetrahydrofuran andtrifluoroacetic acid.

Yield: 72% of theory,

Melting point: 82°-85° C.

Example N

2-Hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

4.6 g (0.033 mol) of Urotropine are added to a solution of 9 g (0.033mol) of 2-trifluoromethyl-4-bromoacetyl-thiazole in 30 ml of methylenechloride at 10° C., while stirring and cooling. A dense paste ofcrystals separates out after a few seconds. The mixture is cooled to0°-3° C. and, after 20 minutes, the precipitate is filtered off withsuction and washed with ether. Colourless crystals are obtained afterdrying at 40° C.

Yield: 11.1 g (81.3% of theory),

M.p.: 134°-137° C.

This urotropine salt is dissolved in 330 ml of ethanol and heated toboiling together with a solution of 70 ml of concentrated hydrochloricacid in 600 ml of water for 2 hours. The mixture is then evaporated todryness. the solid residue which is thus obtained is dissolved in 300 mlof methanol, cooled to 0° C. and 2.4 g of sodium hydrogen carbonate and,in small portions, 4.2 g of sodium borohydride are successively added.After 2 hours 30 ml of 30% strength sodium hydroxide solution are added,and the mixture is then stirred for 20 minutes. After dilution with 200ml of water and extraction by shaking several times with methylenechloride, the organic phase is dried over sodium sulphate, andconcentrated, and the residue is purified on a silica gel column usingmethanol as eluant.

Yield: 2.9 g (51% of theory),

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=7.675 ppm (s, 1H)

Example O

2-(2-Trifluoromethyl-thiazol-4-yl)morpholine

A solution of 0.9 g (0.036 mol) of2-(2-trifluoromethyl-thiazol-4-yl)morpholin-5-one in 40 ml oftetrahydrofuran at 3° C. is mixed with 1.35 g (0.036 mol) of sodiumborohydride. Then, at 5°-8° C., very slowly and with vigorous stirring2.43 g (0.036 mol) of glacial acetic acid dissolved in 20 ml oftetrahydrofuran are added dropwise. The cooling is removed after 2hours, and the mixture is stirred at room temperature for 16 hours.After evaporation to dryness, the resulting residue is mixed with 15 mlof 20% strength hydrochloric acid, and the mixture is heated at 90° C.for 30 minutes. It is then evaporated to dryness, the resulting productis taken up in water, and the solution is made alkaline with sodiumcarbonate solution. The mixture is then extracted several times withmethylene chloride, the organic phase is dried over sodium sulphate andconcentrated, and the residue is purified on a silica gel column usingethyl acetate/methanol =8:2 as eluant.

Yield: 0.56 g (65% of theory),

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=4.750 ppm (dd, ═CH--O)

Example P

2-Hydroxy-2-(2-phenyl-thiazol-4-yl)ethanamine

34.2 g (0.3 mol) of Trifluoroacetic acid in 60 ml of absolutetetrahydrofuran are added dropwise to a suspension of 11.4 g (0.3 mol)of sodium borohydride in 200 ml of absolute tetrahydrofuran whilecooling in ice. Then 13 g (0.06 mol) of2-phenyl-4-formyl-thiazole-cyanohydrin are introduced in portions, andthe mixture is then stirred at room temperature for 20 hours. Thesolvent is removed, 100 g of ice are cautiously added to the residue,and the mixture is acidified with dilute hydrochloric acid and heated ona steam bath for 1 hour. The mixture is cooled to room temperature, madealkaline with ammonia solution and extracted with chloroform. Theextract is dried over sodium sulphate and concentrated and the residueis purified on a silica gel column using methanol as eluant.

Yield: 10.2 g (77.3% of theory),

M.p.: 92°-94° C.

    ______________________________________                                        Calculated:                                                                              C     59.97    H   5.49   N   12.71                                Found:           60.15        5.61       12.83                                ______________________________________                                    

Example Q

2-Hydroxy-2-(thiazol-4-yl)ethanamine

Prepared analogously to Example P by reaction of 4-formyl-thiazole withsodium borohydride and trifluoroacetic acid in tetrahydrofuran. Theproduct obtained by extraction with methylene chloride is purified on asilica gel column using methanol as eluant.

Yield: 19% of theory

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=4.880 ppm (dd, ═CHOH)

Example R

2-Hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine

Prepared analogously to Example P by reaction of2-methyl-4-formyl-thiazole with sodium borohydride and trifluoroaceticacid in tetrahydrofuran.

Yield: 63% of theory,

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=7.150 ppm (s, 1H)

Example S

2-(2-Trifluoromethyl-thiazol-4-yl)morpholin-5-one

0.3 g (0.0064 mol) of a dispersion of sodium hydride (50-55% in oil) isadded in small portions to a stirred solution of 1 g (0.0047 mol) of2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine in 15 ml oftoluene at 30° C. After 1 hour a solution of 0.55 g (0.0045 mol) ofethyl chloroacetate in 2 ml of toluene is added dropwise. After 2 hoursfirst 1 ml of ethanol and then 4 ml of water are added dropwise. Themixture is then acidified with hydrochloric acid and extracted severaltimes with methylene chloride, and the extract is dried over sodiumsulphate. The resulting product is purified on a silica gel column usingethyl acetate/methanol =1/1 as eluant and, after evaporation to dryness,digested with a little ether.

Yield: 0.36 g (32% of theory),

Melting point: 139°-141° C.

Example T

2-(2-Methyl-thiazol-4-yl)morpholin-5-one

Prepared analogously to Example S by reaction of2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with ethyl chloroacetateand purification on a silica gel column using ethyl acetate/methanol=19:1 as eluant.

Yield: 29% of theory,

M.p.: 125°-126° C.

    ______________________________________                                        Calculated:                                                                            C      48.47  H    5.08 N    14.13                                                                              S    16.17                         Found           48.63       5.07      14.10     16.47                         ______________________________________                                    

Example U

2-(2-Methyl-thiazol-4-yl)morpholine

Prepared analogously to Example O by reduction of2-(2-methyl-thiazol-4-yl)morpholin-5-one with lithium aluminium hydrideand purification of the base on a silica gel column withchloroform/methanol/ammonia =93:7:0.7 as eluant.

Yield: 46% of theory,

    ______________________________________                                        Calculated:                                                                            C      52.15  H    6.56 N    15.20                                                                              S    17.40                         Found           52.37       6.52      15.27     17.32                         ______________________________________                                    

Example V

2-Hydroxy-2-(2-methyl-thiazol-5-yl)ethanamine

a) 2-Methyl-5-formyl-thiazole-cyanohydrin

0.5 g (0.004 mol) of 2-Methyl-5-formyl-thiazole is dissolved in 3 ml ofwater and the solution is cooled to 15° C. 1 g of potassium dihydrogenphosphate and 0.4 g of sodium cyanide are successively added. Acolourless product precipitates out almost immediately and is stirred at10° C. for 25 minutes and then filtered off with suction. The resultingcrude product is further reacted without further purification.

Yield: 0.5 g (81% of theory)

b) 2-Hydroxy-2-(2-methyl-thiazol-5-yl)ethanamine

Prepared analogously to Example P by reaction of2-methyl-5-formyl-thiazole-cyanohydrin in tetrahydrofuran with sodiumborohydride and trifluoroacetic acid. The base is purified on a silicagel column using methanol as eluant and is used as the crude product forfurther reactions.

Yield: 87% of theory

Example W

2-(N,N-Dimethylamino)-4-bromoacetyl-thiazole

133.5 g of Dibromodiacetyl in 2.5 l of ether are boiled under reflux ina soxhlet apparatus with 57 g of N,N-dimethylthiourea for 2.5 days.After the reaction mixture has been cooled and concentrated, theresulting residue is taken up in water, and the solution is neutralisedwith saturated sodium bicarbonate solution and extracted several timeswith methylene chloride. The combined extracts are dried, filtered andconcentrated, and then purification is carried out on a silica gelcolumn using toluene/ethyl acetate =8:2 as eluant.

Yield: 50 g (27.7% of theory),

M.p.: 113°-115° C.

    ______________________________________                                        Calculated:                                                                           C     33.75  H   3.64 N   11.26                                                                              S   12.37                                                                              Br  32.08                     Found:        33.90      3.63     11.25    12.69    32.25                     ______________________________________                                    

Example X

2-Hydroxy-2-(2-methyl-oxazol-4-yl)ethanamine

a) 2-Methyl-4-formyl-oxazole-cyanohydrin

Prepared analogously to Example V by reaction of 6 g (0.0543 mol) of2-methyl-4-formyl-oxazole with 5.45 g (0.112 mol) of sodium cyanide and14.4 g (0.1 mol) of potassium dihydrogen phosphate in 180 ml of waterand 60 ml of dioxan.

Yield: 6.2 g (83% of theory), The substance is oily.

    ______________________________________                                        Calculated:                                                                              C     52.17    H   4.37   N   20.28                                Found:           52.08        4.50       19.98                                ______________________________________                                    

b) 2-Hydroxy-2-(2-methyl-oxazol-4-yl)ethanamine

Prepared analogously to Example P by reaction of 6 g (0.0435 mol) of2-methyl-4-formyl-oxazole-cyanohydrin with 8.25 g (0.217 mol) of sodiumborohydride in tetrahydrofuran and 24.6 g (0.214 mol) of trifluoroaceticacid.

Yield: 2.7 g (44% of theory), The substance is oily.

    ______________________________________                                        Calculated:                                                                              C     50.69    H   7.09   N   19.70                                Found:           50.32        7.22       19.68                                ______________________________________                                    

¹ H-NMR spectrum (80 MHz) (CDCl₃): δ=7.55 ppm(s, 1H)

Example Y

2-Chloro-4-bromoacetyl-thiazole

7.6 g (6.0344 mol) of 2-Amino-4-bromoacetyl-thiazole are dissolved in 20ml of water and 50 ml of concentrated hydrochloric acid. Now, at 0° C.and with stirring, a solution of 3.44 g (0.0499 mol) of sodium nitritein 15 ml of water is added dropwise. The resulting diazonium saltsolution is then introduced in portions into a vigorously stirred coldsolution of 4.93 g (0.0449 mol) of copper(I) chloride in 15 ml ofconcentrated hydrochloric acid, and the mixture is stirred at roomtemperature for 20 hours. It is then diluted with 100 ml of water andextracted with ether. The ether extract is dried over sodium sulphateand evaporated. For purification, the crude product is purified on asilica gel column using methylene chloride as the eluant.

Yield: 4 g (48% of theory),

M.p.: 72° C.

    ______________________________________                                        Calculated:                                                                              C     24.96    H   1.25   N   5.82                                 Found:           25.12        1.30       6.00                                 ______________________________________                                    

Example Z

2-Piperidino-4-bromoacetyl-thiazole

7.2 g (0.05 mol) of Piperidino-thiourea are heated to reflux in asoxhlet apparatus for 10 hours with a solution of 12.2 g (0.05 mol) ofdibromodiacetyl in 1 l of ether. The precipitated yellow compound isfiltered off with suction and dissolved in 500 ml of chloroform, and thechloroform solution is extracted with 400 ml of saturated sodiumbicarbonate solution. The chloroform solution is then dried over sodiumsulphate and evaporated. The crude product is purified on a silica gelcolumn using toluene as eluant.

Yield: 7.5 g (52% of theory),

M.p.: 78°-80° C.

    ______________________________________                                        Calculated:                                                                            C      41.53  H    4.52 N    9.68 Br   27.63                         Found:          41.80       4.47      9.40      27.57                         ______________________________________                                    

Example ZA

2-Methoxy-2-(2-methyl-thiazol-4-yl)ethanamine

Prepared analogously to Example L by reduction of4-(α-cyano-α-methoxymethyl)-2-methyl-thiazole [obtained from4-dimethoxymethyl-2-methyl-thiazole by reaction with trimethylsilylcyanide in ether in the presence of boron trifluoride etherate] usingsodium borohydride in a mixture of tetrahydrofuran and trifluoroaceticacid.

Yield: 80% of theory (oil),

Mass spectrum: Calculated (M+H⁺)=173 Found (M+H⁺)=173

Example ZB

2-(2-Trifluoromethyl-thiazol-4-yl)ethylene oxide

a) 1-(2-Trifluoromethyl-thiazol-4-yl)-1-hydroxy-2-bromoethane

6 g (0.022 mol) of 2-Trifluoromethyl-4-bromoacetylthiazole are dissolvedin 150 ml of methanol, and the solution is cooled to 10° C. and 0.63 gof sodium borohydride is added. After 15 minutes ice is added, and themixture is acidified with hydrochloric acid, made alkaline with ammoniaand extracted by shaking with methylene chloride. The organic phase isdried over sodium sulphate, filtered and concentrated. An oil isobtained and is reacted further as the crude product.

Yield: 5.4 g (89% of theory)

¹ H NMR spectrum (80 MHz) (CDCl₃): δ=7.7 ppm (s, 1H)

b) 2-(2-Trifluoromethyl-thiazol-4-yl)ethylene oxide

5 g (0.018 mol) of1-(2-Trifluoromethyl-thiazol-4-yl)-1-hydroxy-2-bromoethane are suspendedin 4 ml of 50% strength sodium hydroxide solution and stirred for 5minutes. The mixture is then diluted with ice-water and extracted byshaking with methylene chloride. The organic phase is dried over sodiumsulphate and concentrated in vacuo at 20° C., and the resulting oil ispurified on a silica gel column using methylene chloride as eluant.

Yield: 2.15 g (67% of theory),

¹ H NMR spectrum (80 MHz) (CDCl₃): δ=7.5 ppm(s, 1H)

Example ZC

2-(2-Methyl-thiazol-4-yl)ethylene oxide

10.2 g (0.048 mol) of Trimethylsulphonium iodide are dissolved in 42 mlof dimethyl sulphoxide and added dropwise to a stirred solution, whichis maintained at 0° C., of 1.14 g of sodium hydride in 50 ml of dimethylsulphoxide/tetrahydrofuran (1:1). After 60 minutes, a solution of 6.1 gof 2-methyl-4-formyl-thiazole in 25 ml of tetrahydrofuran is addeddropwise at 0° C., and the mixture is stirred at room temperature for 3hours. It is then cooled to 0° C., 9.6 ml of water are added dropwise,and the mixture is extracted with ether. The ethereal phase is extractedby shaking 2× with water, dried and concentrated. The resulting oil ispurified on a silica gel column using toluene/ ethyl acetate (65:35) aseluant.

Yield: 1.6 g (24% of theory),

¹ H NMR spectrum (80 MHz) (CDCl₃): δ=7.1 ppm(s, 1H)

Example 1

N-[2-(4-Carbomethoxyphenyl)-1-methylethyl]-N-benzyl-2-hydroxy-2-(2-benzoylamino-thiazol-4-yl)ethanamine

3.5 g (0.011 mol) of 2-Benzoylamino-4-bromoacetyl-thiazole are dissolvedin 20 ml of dimethylformamide and added dropwise to a stirred solution,at room temperature, of 2.6 g (0.092 mol) ofN-benzyl-2-(4-carbomethoxyphenyl)-1-methylethylamine and 1.1 g (0.011mol) of triethylamine dissolved in 40 ml of dimethylformamide. After 1.5hours ice/water is added, and the mixture is extracted with methylenechloride. The extract is dried over sodium sulphate and concentrated.The resulting amino-ketone is taken up in 100 ml of methanol and at roomtemperature, 0.6 g of sodium borohydride is added. After 1 hour themixture is evaporated to dryness, water is added, and hydrochloric acidis used to acidify. After 10 minutes the mixture is made alkaline withammonia and extracted with methylene chloride. The extract is dried oversodium sulphate, concentrated and purified on a silica gel column usingtoluene/ethyl acetate =8.2 as eluant.

Yield: 1.4 g (29% of theory)

    ______________________________________                                        Calculated:                                                                              C     68.03    H   5.90   N   7.93                                 Found:           68.13        6.11       7.88                                 ______________________________________                                    

¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=6.875 ppm (s, 1H)

Example 2

N-[2-(4-Carboxyphenyl)-1-methylethyl]-N-benzyl-2-hydroxy-2-(2-amino-thiazol-4)ethanamine

13.6 ml (0.0136 mol) of 1N sodium hydroxide solution are added dropwiseat room temperature to a solution of 1.5 g (0.0034 mol) ofN-[2-(4-carbomethoxyphenyl)-1-methyl-ethyl]-N-benzyl-2-hydroxy-2-(2-amino-thiazol-4-yl)-ethanaminein dioxan/methanol =1:1 within 10 minutes, with stirring. After 1 hour20 ml of water are added dropwise sufficiently slowly that a solution isalways maintained. After 16 hours 13.5 ml (0.0136 mol) of 1Nhydrochloric acid are added, and the mixture is extracted with methylenechloride which is dried over sodium sulphate and evaporated to dryness,and the resulting base is purified on a silica gel column using ethylacetate/methanol =9:1.

Yield: 0.36 g (26% of theory),

    ______________________________________                                        Calculated:                                                                              C     64.21    H   6.12   N   10.21                                Found:           64.12        6.12        9.99                                ______________________________________                                    

¹ H NMR spectrum (DMSO): δ=6.250 ppm (s, 1H)

Example 3

N-[2-(4-Carboethoxyphenyl)ethyl]-2-hydroxy-2-(2-benzoylamino-thiazol-4-yl)ethanamine

9.6 g (0.03 mol) of 2-Benzoylamino-4-bromoacetyl-thiazole are dissolvedin 100 ml of methylene chloride and, while stirring at room temperature,added dropwise to a solution of 11.5 g (0.06 mol) of2-(4-carboethoxyphenyl)ethylamine in 150 ml of methylene chloride. After1.5 hours, the mixture is cooled to 5° C., diluted with 200 ml ofmethanol and, for the reduction of the resulting amino-ketone, 3 g ofsodium borohydride are added in small portions at 0°-5° C. After 3 hoursthe solution is evaporated to dryness, ice/water is added, andhydrochloric acid is used to acidify. After 10 minutes the mixture ismade alkaline with sodium bicarbonate solution and extracted withmethylene chloride. The extract is dried over sodium sulphate,concentrated and purified on a silica gel column usingchloroform/methanol =9:1, with the addition of 2% ammonia-saturatedethanol, as eluant. The resulting product is induced to crystallise withpetroleum ether.

Yield: 3.4 g (26% of theory),

M.p.: 83°-85° C.

    ______________________________________                                        Calculated:                                                                              C     62.85    H   5.73   N   9.56                                 Found:           62.75        5.78       9.41                                 ______________________________________                                    

Example 4

N-[2-(4-Carboxyphenyl)ethyl]-2-hydroxy-2-(2-benzoylamino-thiazol-4-yl)ethanamine

Prepared analogously to Example 2 by reaction ofN-[2-(4-carboethoxyphenyl)ethyl]-2-hydroxy-2-(2-benzoylamino-thiazol-4-yl)ethanaminewith 1N sodium hydroxide solution, followed by purification of the crudeproduct on a silica gel column using chloroform/methanol =1:1 andtrituration with water/ethanol =9:1.

Yield: 36% of theory,

M.p.: 143°-145° C. (decomp.)

    ______________________________________                                        Calculated:                                                                              C     61.29    H   5.14   N   10.14                                Found:           61.19        5.18       10.06                                ______________________________________                                    

Example 5

N-[2-(4-Carboethoxyphenyl)ethyl]-2-hydroxy-2-(2-benzoylamino-4-methyl-thiazol-5-yl)ethanamine

Prepared analogously to Example 3 by reaction of2-(4-carboethoxyphenyl)ethylamine and stoichiometric amounts oftriethylamine with 2-benzoylamino-4-methyl-5-bromoacetyl-thiazole,followed by reduction and purification of the base on a silica gelcolumn using chloroform/methanol =9:1 as eluant and trituration withpetroleum ether.

Yield: 33% of theory,

M.p.: 96°-98° C.

    ______________________________________                                        Calculated:                                                                              C     63.55    H   6.00   N   9.26                                 Found:           63.45        5.85       9.19                                 ______________________________________                                    

Example 6

N-[2-(4-Carboethoxyphenyl)ethyl]-2-hydroxy-2-(2-acetylamino-4-methyl-thiazol-5-yl)ethanamine

Prepared analogously to Example 3 by reaction of2-(4-carboethoxyphenyl)ethylamine and stoichiometric amounts oftriethylamine with 2-acetylamino-4-methyl-5-bromoacetyl-thiazole,followed by reduction and purification of the base on a silica gelcolumn using ethyl acetate/methanol =19:1 as eluant and trituration withether.

Yield: 33% of theory,

M.p.: 97°-99° C.

    ______________________________________                                        Calculated:                                                                              C     58.29    H   6.44   N   10.73                                Found:           58.40        6.58       10.61                                ______________________________________                                    

Example 7

N-[2-(4-Carboxyphenyl)ethyl]-2-hydroxy-2-(2-acetylamino-4-methyl-thiazol-5-yl)ethanamine

Prepared analogously to Example 2 by reaction ofN-[2-(4-carboethoxyphenyl)ethyl]-2-hydroxy-2-(2-acetylamino-4-methyl-thiazol-5-yl)ethanaminewith 1N sodium hydroxide solution. After neutralisation with 1Nhydrochloric acid, the mixture is evaporated to dryness, and the residueis recrystallised from 10 ml of water.

Yield: 80% of theory,

M.p.: 156°-158° C.

    ______________________________________                                        Calculated:                                                                              C     56.18    H   5.83   N   11.56                                Found:           56.20        5.95       11.61                                ______________________________________                                    

Example 8

N-[2-(4-Carboethoxyphenyl)ethyl]-2-hydroxy-2-(2-amino-4-methyl-thiazol-5-yl)ethanaminedihydrochloride

3 g (0.013 mol) of 2-Amino-4-methyl-5-bromoacetyl-thiazole are added insmall portions to a stirred solution of 5.2 g (0.026 mol) oftriethylamine in 300 ml of tetrahydrofuran at room temperature. After 2hours the mixture is evaporated to dryness. The resulting residue isdissolved in ethanol and, for the reduction of the amino-ketone whichhas formed, 1.5 g of sodium borohydride are added in small portionswhile stirring at 15° C. After 16 hours the solution is evaporated todryness, water is added, and the mixture is acidified with hydrochloricacid. It is then made alkaline with ammonia and extracted with methylenechloride. The extract is dried over sodium sulphate, concentrated andpurified on a silica gel column using chloroform/methanol =8:2 aseluant. The resulting base is dissolved in ethanol, converted into thedihydrochloride with isopropanolic hydrochloric acid and acetone, andthe product is washed with ether.

Yield: 3.5 g (64% of theory),

M.p.: 160° C.

    ______________________________________                                        Calculated:                                                                              C     48.34    H   5.97   N   9.95                                 Found:           48.23        6.20       9.97                                 ______________________________________                                    

Example 9

N-[2-(4-Carboxyphenyl)ethyl]-2-hydroxy-2-(2-amino-thiazol-4-yl)ethanaminedihydrochloride

1.5 g (0.0043 mol) ofN-[2-(4-Carboxyphenyl)ethyl-2-hydroxy-2-(2-acetylamino-thiazol-4-yl)ethanamineare dissolved in 30 ml of 1N hydrochloric acid, and the solution isheated at 90° C. for 2.5 hours and then evaporated to dryness. Theremaining residue is recrystallised from a mixture of 50 ml of ethanoland 3 ml of water, and the resulting crystals are washed with ether.

Yield: 1.4 g (85% of theory),

M.p.: 218°-219° C.

    ______________________________________                                        Calculated:                                                                              C     44.21    H   5.04   N   11.05                                Found:           44.40        5.17       10.94                                ______________________________________                                    

Example 10

N-[2-(4-Carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-acetylamino-thiazol-4-yl)ethanaminehydrochloride

Prepared analogously to Example 3 by reaction of2-(4-carbomethoxyphenyl)-1-methyl-ethanamine and triethylamine intetrahydrofuran with 2-acetylamino-4-bromoacetyl-thiazole, followed byreduction and purification of the base on a silica gel column usingethyl acetate/methanol =9:1 as eluant and precipitating thehydrochloride with isopropanolic hydrochloric acid.

Yield: 36% of theory,

M.p.: 118°-120° C.

    ______________________________________                                        Calculated:                                                                              C     52.23    H   5.84   N   10.15                                Found:           51.98        6.01        9.97                                ______________________________________                                    

According to the ¹ H NMR spectrum (400 MHz), the product is anapproximately 35:65 mixture of diastereomers.

Example 11

N-[2-(4-Carboxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-amino-thiazol-4-yl)ethanaminedihydrochloride

Prepared analogously to Example 9 by reaction ofN-[2-(4-carboxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-acetylamino-thiazol-4-yl)ethanamineand 1N hydrochloric acid.

Yield: 79% of theory,

M.p.: 167° C.

    ______________________________________                                        Calculated:                                                                              C     45.69    H   5.37   N   10.66                                Found:           45.49        5.51       10.54                                ______________________________________                                    

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 40:60 diastereomer mixture.

Example 12

N-[2-(4-Carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

1.3 g (0.0062 mol) of 2-(2-trifluoromethyl-thiazol-4-yl)glyoxal and 1.2g (0.0057 mol) of 2-(4-carboethoxy-phenyl)-1-methyl-ethanamine are mixedat 50° C. and stirred at room temperature for 4 hours. For the reductionof the resulting Schiff's base, 0.75 g of sodium borohydride is added inportions at 20 ° C., and the mixture is stirred for 16 hours. It is thenpoured onto ice, and the mixture is acidified with hydrochloric acid,made alkaline with sodium bicarbonate solution and extracted withmethylene chloride. The extract is dried over sodium sulphate,concentrated and purified on a silica gel column using methylenechloride/methanol =40:1 as eluant.

Yield: 1.5 g (68% of theory),

    ______________________________________                                        Calculated:                                                                              C     52.57    H   4.93   N   7.21                                 Found:           52.71        5.08       7.30                                 ______________________________________                                    

¹ H NMR spectrum (CDCl₃): δ=4.735 ppm (dd, ═CH--OH); δ=4.895 ppm (dd,═CH--OH)

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 60:40 diastereomer mixture.

Example 13

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-phenyl-thiazol-4-yl)ethanamine

1.32 g (0.006 mol) of 2-Hydroxy-2-(2-phenyl-thiazol-4-yl)ethanamine and1.33 g (0.006 mol) of 1-(4-carbomethoxymethoxyphenyl)-propan-2-one aredissolved in 40 ml of absolute methanol, and 0.34 ml (0.006 mol) ofglacial acetic acid and 0.37 g (0.006 mol) of sodium cyanoborohydrideare added and the mixture is stirred at room temperature for 20 hours.It is then poured onto ice, and the mixture is acidified withhydrochloric acid, made alkaline with sodium bicarbonate solution andextracted with chloroform. The extract is dried over sodium sulphate,concentrated and purified on a silica gel column using ethylacetate/methanol =9:1 as eluant.

Yield: 2.2 g (86% of theory)

    ______________________________________                                        Calculated:                                                                            C      64.76  H    6.14 N    6.56 S    7.51                          Found:          64.50       6.42      6.39      7.30                          ______________________________________                                    

¹ H NMR spectrum (CDCl₃): δ=4.88 ppm (dd, ═CH--OH); δ=4.93 ppm (dd,═CH--OH)

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 14

N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine

1 g (0.0027 mol) ofN-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamineis dissolved in 5 ml of methanol and stirred with 5 of concentratedammonia at room temperature for 3 hours. The mixture is then dilutedwith water and extracted with methylene chloride. The extract is driedover sodium sulphate, concentrated and purified on a silica gel columnusing ethyl acetate/methanol =9:1 as eluant.

Yield: 0.76 (81% of theory),

M.p.: 148° C.

    ______________________________________                                        Calculated:                                                                              C     58.43    H   6.63   N   12.02                                Found:           58.62        6.69       12.00                                ______________________________________                                    

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 25:75 diastereomer mixture.

Example 15

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

Prepared analogously to Example 3 by reaction of2-trifluoromethyl-4-bromoacetylthiazole and2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethylamine, followed byreduction and purification of the base on a silica gel column usingmethylene chloride/methanol =9:1 as eluant.

Yield: 10% of theory,

    ______________________________________                                        Calculated:                                                                              C     51.79    H   5.31   N   10.17                                Found:           51.79        5.55       10.91                                ______________________________________                                    

¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=7.575 ppm (s, 1H), δ=7.595 ppm (s,1H);

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 16

N-[2-(4-Carboxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

Prepared analogously to Example 2 by reaction ofN-[2-(4-carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanaminewith 1N sodium hydroxide solution. After neutralisation withhydrochloric acid, the mixture is evaporated to dryness and the residueis treated with a mixture of ethyl acetate/ethanol =6:1. The extract isevaporated to dryness and the residue is triturated with 5 ml of water.The water is decanted off and the remaining residue is taken up inmethanol, the solution is evaporated to dryness, and the residue istriturated with ether and filtered off with suction.

Yield: 52% of theory,

M.p.: 107°-109° C.,

    ______________________________________                                        Calculated:                                                                              C     51.33    H   4.58   N   7.48                                 Found:           51.41        4.74       7.42                                 ______________________________________                                    

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 60:40 diastereomer mixture.

Example 17

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

Prepared analogously to Example 13 by reaction of2-(2-trifluoromethyl-thiazol-4-yl)morpholine with1-(4-carbomethoxymethoxyphenyl)propan-2-one followed by purification ofthe base on a silica gel column using toluene/ethyl acetate =8:2 aseluant.

Yield: 54% of theory,

    ______________________________________                                        Calculated:                                                                              C     54.04    H   5.22   N   6.30                                 Found:           54.28        5.24       6.46                                 ______________________________________                                    

¹ H NMR spectrum (CDCl₃): δ=7.610 ppm (s, 1H); δ=7.575 ppm (s, 1H)

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 18

Methyl3-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidine-carboxylate

0.52 g (0.0012 mol) ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamineand 0.211 g (0.0024 mol) of methyl glyoxylate and 25 ml toluene areheated at 120° C. for 10 minutes and then boiled under a water trap for1 hour. The solution is cooled, 50 ml of ethyl acetate are added, andthe mixture is shaken with 30 ml of water. The organic phase isseparated off, dried over sodium sulphate and concentrated. The residueis purified on a laboratory size B prepacked column (supplied by Merck)using toluene/ethyl acetate =20:1.5 as eluant. Fraction A (diastereomerpairs A and B),

Yield: 90 mg (15.4% of theory), ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=5.10ppm (s, 1H); δ=5.24 ppm (s, 1H)

According to ¹ H NMR spectrum (400 MHz) the product is an approximately50:50 diastereomer mixture.

Fraction B (diastereomer pairs C and D):

Yield: 110 mg (18.8% of theory),

¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=4.97 ppm (s, 1H); δ=5.21 ppm (s, 1H)

According to ¹ H NMR spectrum (400 MHz) the product is an approximately50:50 diastereomer mixture.

Example 19

Methyl3-[2-(4-carbomethoxyphenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate

Prepared analogously to Example 18 by reaction ofN-[2-(4-carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanaminewith methyl glyoxylate.

Fraction A (diastereomer pairs A and B):

Yield: 25% of theory,

¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=5.07 ppm (s, 1H) δ=5.26 ppm (s, 1H)

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 45:55 diastereomer mixture.

Fraction B (diastereomer pairs C and D):

Yield: 23% of theory,

¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=5.08 ppm (s, 1H); δ=5.22 ppm (s, 1H)

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 35:65 diastereomer mixture.

Example 20

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

Prepared analogously to Example 3 by reaction of2-(4-carbomethoxymethoxyphenyl)-1-methyl-ethanamine with2-trifluoromethyl-4-bromoacetyl-thiazole, followed by reduction andpurification of the base on a silica gel column with methylenechloride/methanol =20:1 as eluant.

Yield: 51% of theory,

    ______________________________________                                        Calculated:                                                                              C     51.66    H   5.06   N   6.70                                 Found:           51.40        5.14       6.64                                 ______________________________________                                    

¹ H NMR spectrum (CDCl₃): δ=4.835 ppm (dd, ═CH--OH); δ=4.895 ppm (dd,═CH--OH)

According to ¹ H NMR spectrum (400 MHz) the product is an approximately60:40 diastereomer mixture.

Example 21

N-[2-(4-Carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(4-methyl-oxazol-5-yl)ethanaminedihydrochloride

2.6 g (0.009 mol) of 4-Methyl-5-bromoacetyl-oxazole and 1.16 g (0.009mol) of N,N-diisopropyl-ethylamine are dissolved in 50 ml of methylenechloride. This solution is added dropwise, within 20 minutes to 3.47 g(0.018 mol) of 2-(4-carbomethoxyphenyl)-1-methylethylamine in 100 ml ofmethylene chloride, and the mixture is stirred at room temperature for 2hours and at 35° C. for 1 hour. The reaction solution is cooled in anice bath, and 150 ml of methanol are added. Then, for the reduction ofthe resulting amino-ketone, 1 g of sodium borohydride is added inportions over 30 minutes, and the mixture is stirred at room temperaturefor 20 hours and then evaporated. Ice-water is then added to theresidue, and the mixture is acidified with hydrochloric acid, madealkaline with concentrated aqueous ammonia and extracted withchloroform. The extract is dried over sodium sulphate, concentrated andpurified on a silica gel column using ethyl acetate/methanol =9:1 aseluant. The hydrochloride is then precipitated with etherealhydrochloric acid.

Yield: 1.1 g (31% of theory),

M.p.: 80° C. (decomp.)

    ______________________________________                                        Calculated:                                                                            C      52.17  H    6.18 N    7.13 Cl   18.14                         Found:          52.00       6.10      6.90      17.90                         ______________________________________                                    

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 22

N-[2-(4-Carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(thiazol-4-yl)ethanamine

Prepared analogously to Example 3 by reaction of2-(4-carbomethoxyphenyl)-1-methylethylamine with 4-bromoacetyl-thiazole,followed by reduction and purification of the base on a silica gel plateusing ethyl acetate/methanol =8:2 as eluant.

Yield: 9% of theory,

    ______________________________________                                        Calculated:                                                                              C     59.97    H   6.29   N   8.75                                 Found:           60.09        6.01       8.56                                 ______________________________________                                    

¹ H NMR spectrum (CDCl₃): δ=4.900-4.970 ppm (m, ═CH--OH);

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 60:40 diastereomer mixture.

Example 23

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-methyl-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

Prepared analogously to Example 3 by reaction of2-trifluoromethyl-4-bromoacetyl-thiazole andN-methyl-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine, followed byreduction and purification of the base on a silica gel column usingethyl acetate/methanol =40:1 as eluant.

Yield: 53% of theory,

    ______________________________________                                        Calculated:                                                                              C     52.77    H   5.36   N   6.48                                 Found:           53.00        5.06       6.64                                 ______________________________________                                    

¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=7.555 ppm (s, 1H); δ=7.575 ppm (s,1H)

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 24

N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

Prepared analogously to Example 14 by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanaminewith concentrated ammonia followed by purification of the base on asilica gel column using methylene chloride/methanol =9:1 as eluant.

Yield: 65% of theory,

    ______________________________________                                        Calculated:                                                                              C     50.61    H   5.00   N   10.42                                Found:           50.43        5.19       10.37                                ______________________________________                                    

¹ H NMR spectrum (CDCl₃): δ=4.850 ppm (dd, ═CH--OH); δ=4.775 ppm (dd,═CH--OH)

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 60:40 diastereomer mixture.

Example 25

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine

Prepared analogously to Example 13 by reaction of2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with1-(4-carbomethoxymethoxyphenyl)propan-2-one followed by purification ofthe base on a silica gel column using ethyl acetate/methanol =9:1 aseluant.

Yield: 55% of theory,

    ______________________________________                                        Calculated:                                                                              C     59.32    H   6.64   N   7.69                                 Found:           59.20        6.45       7.91                                 ______________________________________                                    

¹ H NMR spectrum (CDCl₃): δ=4.825 ppm (dd, ═CH--OH); δ=4.775 ppm (dd,═CH--OH);

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 26

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(thiazol-4-yl)ethanamine

Prepared analogously to Example 13 by reaction of2-hydroxy-2-thiazol-4-yl)ethylamine with1-(4-carbomethoxymethoxyphenyl)propan-2-one followed by purification ofthe base on a silica gel column using ethyl acetate/methanol =8:2 aseluant.

Yield: 48% of theory,

    ______________________________________                                        Calculated:                                                                              C     58.26    H   6.33   N   8.00                                 Found:           58.41        6.36       8.22                                 ______________________________________                                    

¹ H NMR spectrum (CDCl₃): δ=4.945 ppm (dd, ═CH--OH); δ=4.900 ppm (dd,═CH--OH)

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 27

N-[2-(4-Carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2,5-dimethyl-oxazol-4-yl)ethanaminedihydrochloride

Prepared analogously to Example 21 by reaction of2,5-dimethyl-4-bromoacetyl-oxazole with2-(4-carbomethoxyphenyl)-1-methylethylamine, followed by reduction andprecipitation of the dihydrochloride using ethereal hydrochloric acid.

Yield: 47% of theory,

Melting point: 78° C. (decomp.)

    ______________________________________                                        Calculated:                                                                            C      53.33  H    6.46 N    6.90 Cl   17.51                         Found:          53.10       6.50      6.80      17.32                         ______________________________________                                    

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 28

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2,5-dimethyl-oxazol-4-yl)ethanaminedihydrochloride

Prepared analogously to Example 21 by reaction of2,5-dimethyl-4-bromoacetyl-oxazole with2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine, followed byreduction and precipitation of the dihydrochloride using etherealhydrochloric acid.

Yield: 47% of theory,

M.p.: 82° C. (decomp.)

    ______________________________________                                        Calculated:                                                                            C      52.41  H    6.48 N    6.43 Cl   16.28                         Found:          52.21       6.55      6.50      16.40                         ______________________________________                                    

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 29

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2,4-dimethyl-thiazol-5-yl)ethanamine

Prepared analogously to Example 3 by reaction of2,4-dimethyl-5-bromoacetyl-thiazole with2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine, followed byreduction and purification of the base on a silica gel column usingethyl acetate/methanol =17:3.

Yield: 45% of theory,

    ______________________________________                                        Calculated:                                                                              C     60.29    H   6.92   N   7.40                                 Found            60.53        6.85       7.60                                 ______________________________________                                    

¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=4.890-4.970 ppm (m, ═CH--OH);

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 53:47 diastereomer mixture.

Example 30

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

Prepared analogously to Example 3 by reaction of2-trifluoromethyl-4-bromoacetyl-thiazole andN-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine.Before the reduction with sodium borohydride, the mixture is heated toboiling for 3 hours to complete the reaction. The base is then purifiedon a silica gel column using ethyl acetate as mobile phase.

Yield: 50% of theory,

    ______________________________________                                        Calculated:                                                                              C     51.94    H   5.45   N   6.06                                 Found:           52.00        5.33       6.09                                 ______________________________________                                    

¹ H NMR spectrum (CDCl₃): δ=0.930 ppm (d, --CH--); δ=0.970 ppm ##STR28##

Example 31

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-5-methyl-oxazol-4-yl)ethanaminehydrochloride

Prepared analogously to Example 21 by reaction of2-trifluoromethyl-5-methyl-4-bromoacetyl-oxazole with2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine followed byreduction. The compound is purified on a silica gel column using ethylacetate/methanol =20:1 as eluant, and then the hydrochloride isprecipitated with ethereal hydrochloric acid.

Yield: 0.43 g (10% of theory),

M.p.: 58° C.

    ______________________________________                                        Calculated:                                                                            C      50.38  H    5.34 N    6.18 Cl   7.82                          Found:          50.58       5.33      5.93      8.20                          ______________________________________                                    

Example 32

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholinePrepared analogously to Example 3 by reaction of 11.6 g (0.043 mol) of2-trifluoromethyl-4-bromoacetyl-thiazole with 23 g (0.086 mol) ofN-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine.To complete the reaction the mixture is heated to boiling for 6 hours.It is then concentrated in vacuo, and the resulting residue is dissolvedin 85 ml of trifluoroacetic acid and, at room temperature, 7 g (0.06mol) of triethylsilane are added. After 90 hours the solution is pouredonto ice, and concentrated ammonia is added,and the mixture is extractedseveral times with methylene chloride. The organic phase is dried oversodium sulphate and concentrated, and the residue is purified on asilica gel column using toluene/ethyl acetate =8/2 as eluant.

Yield: 11 g (58% of theory),

¹ H NMR spectrum: δ=7.610 ppm (s, 1H); 7.578 ppm (s, 1H)

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 43:57 diastereomer mixture.

Example 33

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-5-methyl-thiazol-4-yl)-ethanamine

Prepared analogously to Example 3 by reaction of2-trifluoromethyl-5-methyl-4-bromoacetyl-thiazole with2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine followed byreduction. The compound is purified on a silica gel column using ethylacetate/methanol =9/1 as eluant.

Yield: 8% of theory,

    ______________________________________                                        Calculated:                                                                              C     52.77    H   5.36   N   6.47                                 Found:           52.60        5.44       6.55                                 ______________________________________                                    

¹ N NMR spectrum (CDCl₃): δ=4.765 ppm (dd, ═CH--OH); δ=4.810 ppm (dd,═CH--OH)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 54:46 diastereomer mixture.

Example 34

N-[3-(4-Carboxamidophenyl)-1-methylpropyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

Prepared analogously to Example 13 by reaction of2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with1-(4-carboxamidophenyl)butan-3-one followed by purification of the baseon a silica gel column using ethyl acetate/methanol =5/1 as eluant.

Yield: 26% of theory,

M.p.: 119°-121° C.

    ______________________________________                                        Calculated:                                                                              C     52.70    H   5.20   N   10.85                                Found            52.61        5.35       10.84                                ______________________________________                                    

According to ¹ H NMR spectrum (400 MHz), the product is an approximately50:50 diastereomer mixture.

Example 35

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

Prepared analogously to Example 16 by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine in methanol with 1N sodium hydroxide solution. Afterneutralisation with 1N hydrochloric acid, the mixture is extracted byshaking with methylene chloride, the extract is evaporated to dryness,and the remaining residue is triturated with petroleum ether andfiltered off with suction.

Yield: 94% of theory,

M.p.: 86° C.

    ______________________________________                                        Calculated:                                                                              C     53.01    H   4.92   N   6.51                                 Found:           53.14        4.85       6.54                                 ______________________________________                                    

Example 36

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

Prepared analogously to Example 16 by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine in methanol with 1N sodium hydroxide solution. Afterneutralisation with 1N hydrochloric acid, the mixture is extracted byshaking with methylene chloride, the extract is evaporated to dryness,and the remaining residue is triturated with petroleum ether andfiltered off with suction.

Yield: 50% of theory,

M.p.: 80°-82° C. (decomp.)

    ______________________________________                                        Calculated:                                                                              C     50.49    H   4.74   N   6.93                                 Found:           50.60        4.61       7.04                                 ______________________________________                                    

Example 37

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanaminehydrochloride

Prepared analogously to Example 13 by reaction of2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanamine with1-(4-carbomethoxymethoxyphenyl)-propan-2-one followed by precipitationof the hydrochloride with ethereal hydrochloric acid.

Yield: 43% of theory,

M.p.: 58° C. (decomp.)

    ______________________________________                                        Calculated:                                                                           C     48.45  H   5.26 N   6.64 Cl  16.82                                                                              S   7.60                      Found:        48.48      5.23     6.61     16.67    7.87                      ______________________________________                                    

Example 38

N-[2-(4-(2-Carbomethoxy-1-methylethenyl)phenyl)-1-methylethyl]-2-hydroxy-2-(trifluoromethyl-thiazol-4-yl)ethanamine

Prepared analogously to Example 13 by reaction of2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with1-[4-(2-carbomethoxy-1-methylethenyl) phenyl]-propan-2-one followed bypurification of the base on a silica gel column usingchloroform/methanol/ methanolic ammonia =9.5/0.4/0.1 as eluant.

Yield: 43% of theory,

    ______________________________________                                        Calculated:                                                                            C      56.00  H    5.41 N    6.54 S    7.48                          Found:          56.00       5.57      6.37      7.76                          ______________________________________                                    

According to ¹ H NMR spectrum (400 MHz) the product is an approximately3:4 diastereomer mixture.

Example 39

N-[2-(4-(2-Carbomethoxy-1-methylethenyl)phenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

Prepared analogously to Example 13 by reaction of2-(2-trifluoromethyl-thiazol-4-yl)morpholine with1-[4-(2-carbomethoxy-1-methylethenyl)phenyl]propan-2-one followed bypurification of the base on a silica gel column using chloroform/ethylacetate =19:1 as eluant.

Yield: 29% of theory,

    ______________________________________                                        Calculated:                                                                            C      58.14  H    5.54 N    6.16 S    7.05                          Found:          58.38       5.49      5.96      7.40                          ______________________________________                                    

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 40

N-[2-(4-(2-Carbomethoxy-1-methylethenyl)phenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)-ethanamine

Prepared analogously to Example 13 by reaction of2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with1-[4-(2-carbomethoxy-1-methylethenyl)phenyl]propan-2-one followed bypurification of the base on a silica gel column using toluene/methanol=19:1 as eluant.

Yield: 32% of theory,

    ______________________________________                                        Calculated:                                                                            C      65.97  H    7.05 N    6.99 S    8.01                          Found:          65.70       7.16      6.88      8.05                          ______________________________________                                    

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 41

N-[2-(4-(2-Carbomethoxy-1-methylethenyl)phenyl)-1-methylethyl]-2-(2-methyl-thiazol-4-yl)morpholine

Prepared analogously to Example 13 by reaction of2-(2-methyl-thiazol-4-yl)morpholine with1-[4-(2-carbomethoxy-1-methyl-ethenyl)phenyl]propan-2-one followed bypurification of the base on a silica gel column usingchloroform/methanol/ammonia =9:1:0.1 as eluant.

Yield: 59% of theory,

    ______________________________________                                        Calculated:                                                                            C      64.13  H    7.00 N    7.48 S    8.56                          Found:          63.90       6.86      7.20      8.28                          ______________________________________                                    

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 42

N-[2-(4-Hydroxyphenyl)-1-methylethyl]-2-(2-methyl-thiazol-4-yl)morpholine

Prepared analogously to Example 13 by reaction of2-(2-methyl-thiazol-4-yl)morpholine with 1-4-hydroxyphenyl)-propan-2-onefollowed by purification of the base on a silica gel column usingtoluene/ methanol =9:1 as eluant.

Yield: 46% of theory,

    ______________________________________                                        Calculated:                                                                            C      64.12  H    6.96 N    8.80 S    10.07                         Found:          63.90       7.03      8.73       9.83                         ______________________________________                                    

According to the ¹ H NMR spectrum (400 MHz) the product is anapproximately 50:50 diastereomer mixture.

Example 43

N-[2-(4-Carbomethoxymethoxyphenyl)ethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

Prepared analogously to Example 3 by reaction of2-trifluoromethyl-4-bromoacetyl-thiazole with2-(4-carbomethoxymethoxyphenyl)ethanamine, followed by reduction.

Yield: 15% of theory,

M.p.: 91°-92° C.

    ______________________________________                                        Calculated:                                                                            C      50.49  H    4.74 N    6.93 S    7.93                          Found:          50.74       4.94      6.84      8.10                          ______________________________________                                    

Example 44

N-[3-(4-Carboxamidophenyl)-1-methylpropyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanaminePrepared analogously to Example 13 by reaction of2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with1-(4-carboxamidophenyl)butan-3-one.

Yield: 46% of theory,

M.p.: 94°-95° C.

    ______________________________________                                        Calculated:                                                                            C      61.24  H    6.95 N    12.60                                                                              S    9.61                          Found:          61.50       7.15      12.34     9.65                          ______________________________________                                    

According to the ¹ H NMR spectrum (400 MHz) the product is a 50:50mixture of diastereomers.

Example 45

N-[3-(4-Carboxamidophenyl)-1-methylpropyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

Prepared analogously to Example 32 by reaction ofN-(2-hydroxyethyl)-3-(4-carboxamidophenyl)-1-methylpropylamine with2-trifluoromethyl-4-bromoacetyl-thiazole followed by reduction withtriethylsilane.

Yield: 19.7% of theory,

M.p.: 95°-105° C.

    ______________________________________                                        Calculated:                                                                            C      55.19  H    5.36 N    10.16                                                                              S    7.76                          Found:          55.20       5.45       9.98     7.91                          ______________________________________                                    

¹ H NMR spectrum (CDCl₃): δ=4.74 ppm (dd, 1H) δ=4.815 ppm (dd, 1H)

According to the ¹ H NMR spectrum (400 MHz) the product is a 48:52mixture of diastereomers.

Example 46

N-[2-(4-Carbomethoxymethoxyphenyl)ethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanaminehydrochloride

a)N-(4-Hydroxyphenyl-acetyl)-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine

3.16 g (20 mmol) of 2-Hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine aredissolved in 80 ml of absolute tetrahydrofuran and, successively, 3.84 g(20 mmol) of 4-hydroxy-phenylacetic acid, 6.3 g (24 mmol) oftriphenylphosphine, 5.6 ml (40 mmol) of triethylamine and 2 ml (20 mmol)of carbon tetrachloride are added. After stirring overnight, the mixtureis concentrated, the residue is taken up in 2N hydrochloric acid and thesolution is extracted three times with methylene chloride. The aqueousphase is then adjusted to pH 7 with 2N sodium hydroxide solution andevaporated to dryness. The residue from evaporation is extracted byboiling several times with a mixture of chloroform/methanol (1:1). Theextracts are concentrated, and the residue is purified on a silica gelcolumn using ethyl acetate/methanol =50:1 as eluant.

Yield: 4.4 g of oil (75.9% of theory),

    ______________________________________                                        Calculated:                                                                              C     57.51    H   5.52   N   9.58                                 Found:           57.63        5.59       9.41                                 ______________________________________                                    

b)N-[2-(4-Hydroxyphenyl)ethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanaminehydrochloride

4.2 g (14.4 mmol) ofN-(4-Hydroxyphenyl-acetyl)-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamineare dissolved in 30 ml of absolute tetrahydrofuran, and the solution isadded dropwise to a suspension, which is boiling under reflux, of 1.37 g(36 mmol) of lithium aluminium hydride in 30 ml of absolutetetrahydrofuran. After 1 hour the mixture is cooled, decomposed with 2Nsodium hydroxide solution and concentrated. The residue is then taken upin 20 ml of 2N hydrochloric acid, and the solution is made alkaline withaqueous ammonia. After renewed concentration, the residue is extractedwith hot chloroform/methanol =10:1. The extracts are concentrated andpurified on a silica gel column using ethyl acetate/methanol =4:1 aseluant. Subsequently the hydrochloride is precipitated in ethyl acetateusing ethereal hydrochloric acid.

Yield: 760 mg (19% of theory),

M.p.: 110°-113° C.

    ______________________________________                                        Calculated:                                                                            C      53.41  H    6.08 N    8.90 Cl   11.26                         Found:          53.12       6.04      8.80      11.31                         ______________________________________                                    

c)N-[2-(4-Carbomethoxymethoxyphenyl)ethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanaminehydrochloride

100 mg (2.1 mmol) of Sodium hydride dispersion (50% in paraffin oil) areadded to 280 mg (1 mmol) ofN-[2-(4-hydroxyphenyl)ethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanaminehydrochloride dissolved in 7 ml of absolute dimethyl formamide. Afterstirring at room temperature for 15 minutes, the solution of 153 mg (1mmol) of ethyl bromoacetate in 3 ml of absolute dimethylformamide israpidly added dropwise. The mixture is then stirred overnight, 20 ml ofsaturated sodium bicarbonate solution are added, and extraction withmethylene chloride is carried out. The extracts are dried, concentratedand, after dissolution in ether/methanol, the hydrochloride isprecipitated with ethereal hydrochloric acid.

Yield: 20 mg (21% of theory),

M.p.: 163°-165° C. (decomp.)

    ______________________________________                                        Calculated:                                                                              C     52.78    H   5.99   N   7.24                                 Found:           52.41        5.76       7.32                                 ______________________________________                                    

Example 47

N-[2-(4-Carbomethoxymethoxyphenyl)ethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

a)N-[2-(4-Methoxy-phenyl)ethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

Prepared analogously to Example 32 by reaction ofN-(2-hydroxyethyl)-2-(4-methoxyphenyl)ethanamine with2-trifluoromethyl-4-bromoacetyl-thiazole followed by reduction withtriethylsilane.

Yield: 24% of theory, oil,

    ______________________________________                                        Calculated:                                                                            C      54.82  H    5.14 N    7.52 S    8.61                          Found:          55.00       5.24      7.42      8.86                          ______________________________________                                    

b)N-[2-(4-Carbomethoxymethoxyphenyl)ethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

0.6 g (1.6 mmol) ofN-[2-(4-Methoxyphenyl)ethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholineare heated on a steam bath with 6 ml of 48% strength aqueous hydrobromicacid for 3 hours. The mixture is then concentrated, toluene is added,and the mixture is again evaporated to dryness. The foamy residue isboiled under reflux in 15 ml of acetone with 1.2 g (8.7 mmol) ofpotassium carbonate and 0.3 ml (1.65 mmol) of methyl bromoacetate for 1hour. The mixture is then filtered, the filtrate is concentrated, andthe residue is purified on a silica gel column using toluene/acetone=4:1.

Yield: 0.5 g (72% of theory),

    ______________________________________                                        Calculated:                                                                            C      53.01  H    4.92 N    6.51 S    7.45                          Found:          53.07       4.88      6.72      7.62                          ______________________________________                                    

Example 48

N-[2-(4-Carboethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

a)N-[2-(4-Hydroxphenyl)-1-methylethyl]-2-(2-trifluoromethylthiazol-4-yl)morpholine

Prepared by analogy to Example 22 by reaction of2-trifluoromethyl-4-bromoacetyl-thiazole withN-[2-(4-hydroxyphenyl)-1-methylethyl]-2-hydroxyethanamine followed bypurification of the base on a silica gel column using chloroform/ethylacetate =3:1 as eluant.

Yield: 29% of theory,

    ______________________________________                                        Calculated:                                                                              C     54.83    H   5.14   N   7.52                                 Found:           53.83        5.07       6.93                                 ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is a 50:50mixture of the diastereomers.

b)N-[2-(4-Carboethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

280 mg (0.75 mmol) ofN-[2-(4-hydroxyphenyl-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholineare boiled under reflux for 6 hours with 101 mg (0.82 mmol) of ethylchloroacetate and 113 mg (0.82 mmol) of potassium carbonate in 2 ml ofanhydrous acetone. The mixture is then filtered with suction, theresidue is washed twice with acetone, and the filtrate is concentrated.The crude base is purified on a silica gel column usingchloroform/methanol =20:1 as eluant.

Yield: 50% of theory,

    ______________________________________                                        Calculated:                                                                            C      55.01  H    5.50 N    6.11 S    6.99                          Found:          55.48       5.62      5.85      6.62                          ______________________________________                                    

Example 49

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-isopropyl-thiazol-4-yl)morpholin-6-onehydrochloride

0.194 g (1.27 mmol) of methyl bromoacetate, 0.175 g (1.27 mmol) ofpotassium carbonate and a small crystal of potassium iodide aresuccessively added to a solution of 0.50 g (1.27 mmol) ofN-[2-(4-methoxy-carbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-isopropyl-thiazol-4-yl)ethanaminein 5 ml of anhydrous dimethyl formamide. After stirring at 20° C. for 4hours, the dimethyl formamide is removed by distillation in vacuo, andthe residue is partitioned between chloroform and water. The dried andfiltered chloroform extract is concentrated in vacuo and the residue ispurified by column chromatography on silica gel (toluene/acetone =4/1).

Yield: 0.20 g (36% of theory), viscous oil.

According to the ¹ H-NMR spectrum (400 MHz, CDCl₃ /CD₃ OD) the productis a 50:50 mixture of the diastereomers.

δ=5.59 ppm (dd, ═CH--O--CO--)

δ=5.62 ppm (dd, ═CH--O--CO--)

A hydrochloride is obtained in the form of a foam by treatment of thebase with hydrogen chloride/ether followed by drying at 20° C. and 0.1Torr.

Melting range: 40°-50° C.

    ______________________________________                                        Calculated:                                                                              C     54.44    H   6.27   Cl  8.77                                 (× 1.2                                                                  HCl)                                                                          Found:           54.70        6.57       8.48                                 ______________________________________                                    

Example 50

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-isopropyl-thiazol-4-yl)morpholine

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-isopropyl-thiazol-4-yl)morpholin-5-one

0.60 ml (7.89 mmol) of chloroacetyl chloride is added dropwise to astirred solution of 3.10 g (7.89 mmol) ofN-[2-(4-methoxycarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-isopropyl-thiazol-4-yl)-ethanamineand 1.10 ml (7.89 mmol) of triethylamine in 20 ml of chloroform at 25°C. internal temperature. After the mixture has stood overnight at 20°C., it is concentrated in vacuo, and the resudue is dissolved in 30 mlof anhydrous dimethyl formamide. To this is added 0.888 g (15.78 mmol)of a 55% dispersion of sodium hydride in oil, during which brief foamingis observed. The mixture is stirred at 20° C. for 3 hours, concentratedin vacuo, and the residue is partitioned between water and ether. Theether solution is dried, filtered and concentrated in vacuo, and theoily residue is purified on silica gel (toluene/acetone =4:1).

Yield: 1.40 g (41% of theory),

Melting range: 60°-70° C.

    ______________________________________                                        Calculated:                                                                            C      61.10  H    6.53 N    6.48 S    7.41                          Found:          61.20       6.57      6.77      7.58                          ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz, CDCl₃) the product is a50:50 mixture of the diastereomers.

δ=4.72 ppm (dd, ═CH--0--)

δ=4.85 ppm (dd, ═CH--O--)

b)N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-isopropyl-thiazol-4-yl)morpholine

0.200 g (0.462 mmol)N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-isopropyl-thiazol-4-yl)morpholin-5-oneis added to 0.425 ml (4.56 mmol) of phosphorus oxychloride. After themixture has been stirred at 20° C. for 15 minutes it is concentrated invacuo, and the residue is dissolved in 4 ml of 1,2-dimethoxyethane.After addition of 0.052 g (1.39 mmol) of sodium borohydride and stirringovernight at 20° C., the mixture is concentrated in vacuo and theresidue is partitioned between chloroform and water. After thechloroform solution has been dried and filtered and concentrated it isheated with hydrogen chloride solution at 100° C. for one hour. Afterconcentration in vacuo the residue is partioned between chloroform andaqueous sodium carbonate solution, and the chloroform extract ispurified on silica gel (toluene/acetone =3:1).

Yield: 0.028 g (14.5% of theory),

Calculated: Molecular peak m/e=418

Found: Base peak m/e=239

According to the ¹ H-NMR spectrum (400 MHz, CDCl₃ /CD₃ OD) the productis a 50:50 mixture of the diasetereomers.

δ=4.72 ppm (dd, ═CH--O--)

δ=4.74 ppm (dd, ═CH--O--)

Example 51

N-[2-Carbomethoxyethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-isopropyl-thiazol-4-yl)ethanaminedihydrochloride

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-isopropyl-thiazol-4-yl)ethanamine with1-(4-carbomethoxyethoxyphenyl)-propan-2-one followed by purification ofthe base by column chromatography on silica gel (chloroform/methanol=10:1).

Yield: 89% of theory,

Calculated: Molecular peak m/e=418

Found: Base peak m/e=239

¹ H-NMR spectrum (400 MHz, CDCl₃): δ=4.80 ppm (dd, ═CH--OH) δ=4.84 ppm(dd, ═CH--OH)

According to the ¹ H-NMR spectrum the product is an approximately 50:50mixture of the diastereomers.

To convert the base into the dihydrochloride it treated with hydrogenchloride/diethyl ether. After the ether has been evaporated off in vacuothe product is dried at 20° C. and 0.1 Torr for 3 days.

Melting range: 55°-70° C.

    ______________________________________                                        Calculated:                                                                            C      51.61  H    6.49 N    6.02 S    6.88                          Found:          51.40       6.64      5.86      6.88                          ______________________________________                                    

Example 52

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-propylthiazol-4-yl)ethanaminedihydrochloride

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-propyl-thiazol-4-yl)ethanamine with1-(4-carbomethoxymethoxyphenyl)propan-2-one followed by purification ofthe base by column chromatography on silica gel (chloroform/methanol=10:1).

Yield: 52% of theory,

¹ H-NMR spectrum (400 MHz, CDCl₃ /CD₃ OD): δ=4.72 ppm (dd, ═CH--OH)δ=4.78 ppm (dd, ═CH--OH)

According to the ¹ H-NMR spectrum the product is an approximately 50:50mixture of the diastereomers.

To convert the viscous base into the dihydrochloride it is treated withhydrogen chloride/methanol. After the methanol has been evaporated offin vacuo, the product is dried first at 0.1 Torr and 40°-50° C. and thenovernight at 35° C. and 0.1 Torr over phosphorous pentoxide.

Melting range: 50°-70° C.

    ______________________________________                                        Calculated:                                                                            C      51.61  H    6.49 N    6.02 S    6.88                          Found:          51.38       6.13      6.28      7.00                          ______________________________________                                    

Example 53

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-propyl-thiazol-4-yl)ethanamine

Prepared by analogy to Example 16 by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-propyl-thiazolyl-4-yl)ethanaminein methanol and 1N sodium hydroxide solution. After the mixture has beenneutralised with 1N hydrochloric acid it is concentrated in vacuo, andthe residue is then partitioned between chloroform and water. Thechloroform extract is dried over sodium sulphate, filtered andevaporated in vacuo. The residue from evaporation provides ontrituration with ether a powdery solid which is dried at 50° C. and 0.1Torr for 6 hours.

Yield: 79% of theory,

Melting range: 79°-85° C.

    ______________________________________                                        Calculated:                                                                            C      58.23  H    7.07 N    7.15 S    8.18                          (× 0.75                                                                 H.sub.2 O)                                                                    Found:          58.10       6.75      6.91       8.56.                        ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz, CDCl₃ /CD₃ OD) the productis a 50:50 mixture of the diastereomers.

δ=5.14 ppm (dd, ═CH--OH)

δ=5.17 ppm (dd, ═CH--OH)

Example 54

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-isopropyl-thiazol-4-yl)ethanaminehydrochloride

Prepared by analogy to Example 16 by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-isopropyl-thiazolyl-4-yl)ethanaminein methanol and 1N sodium hydroxide solution. After 1N hydrochloric acidhas been added until pH 6 has been reached, the mixture is concentratedin vacuo, and the residue is partitioned between chloroform and water.The dried and filtered chloroform extract is evaporated in vacuo.Trituration of the residue from evaporation with ether results in afoam-like solid which still contains about 5% chloroform even afterdrying for several hours at 30° C. and 0.1 Torr over phosphorouspentoxide.

Yield: 22% of theory,

Melting range: 80°-90° C.

    ______________________________________                                        Calculated:                                                                            C      54.35  H    6.48 N    6.66 S    9.69                          (× 5%                                                                   CHCl.sub.3)                                                                   Found:          54.19       6.27      6.53      9.26                          ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz, d₆ -DMSO) the product is anapproximately 50:50 mixture of the diastereomers.

δ=5.00 ppm (dd, ═CH--OH)

δ=5.04 ppm (dd, ═CH--OH)

Example 55

N-[2-(4-Methoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanaminehydrochloride

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-trifluoromethyl-thiazolyl-4-yl)ethanamine with4-methoxyphenyl-propan-2-one, followed by purification of a base on asilica gel column using ethyl acetate/methanol =92:8 as eluant andprecipitation of the hydrochloride with ethereal hydrochloric acid.

Yield: 57% of theory,

Melting range: 147°-149° C. (decomp.)

    ______________________________________                                        Calculated:                                                                            C      48.42  H    5.08 N    7.06 Cl   8.93                          Found:          48.65       5.39      7.11      9.19                          ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is a 1:1 mixtureof the diastereomers.

Example 56

3-[2-(4-Methoxyphenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate

Prepared by analogy to Example 18 by reaction ofN-[2-(4-methoxyphenyl)-1-methylethyl]2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanaminewith methyl glyoxylate followed by purification of the base on a silicagel column using chloroform/petroleum ether/ethyl acetate =5:4.5:0.5 aseluant.

Yield: 25% of theory,

    ______________________________________                                        Calculated:                                                                            C      53.02  H    4.92 N    6.51 Cl   7.45                          Found:          53.29       4.86      6.32      7.54                          ______________________________________                                    

Example 57

N-[2-(4-Hydroxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethylthiazol-4-yl)ethanamine

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with4-hydroxyphenyl-propan-2-one followed by purification of the base on asilica gel column using chloroform/methanol =9:1 as eluant.

Yield: 63% of theory,

Melting point: from 77° C., clear melt from 97° C.

    ______________________________________                                        Calculated:                                                                            C      52.01  H    4.95 N    8.09 S    9.26                          Found:          52.05       4.98      8.17      9.19                          ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is a 1:1 mixtureof the diastereomers.

Example 58

N-[2-(4-Hydroxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methylthiazol-4-yl)ethanamine

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with4-hydroxyphenyl-propan-2-one followed by purification of the base on asilica gel column using chloroform/methanol/ammonia =9:1:1 as eluant.

Yield: 52% of theory,

Melting point: 146°-154° C.

    ______________________________________                                        Calculated:                                                                              C 61.62   H 6.89   N 9.58  S 10.97                                 Found:     61.96     6.90     9.65    11.24                                   ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is a 70:30mixture of the diasteromers.

Example 59

N-[2-(4-Methoxyphenyl)-1-methylethyl]-2-(2-trifluoromethylthiazol-4-yl)morpholine

Prepared by analogy to Example 13 by reaction of2-(2-trifluoromethyl-thiazol-4-yl)morpholine with4-methoxyphenyl-propan-2-one followed by purification of the base on asilica gel column using chloroform/ethyl acetate =9:1 as eluant.

Yield: 80% of theory,

Melting point: 146°-154° C.

    ______________________________________                                        Calculated:  C 55.95    H 5.48    N 7.25                                      Found:       56.09      5.62      6.83                                        ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is a 50:50mixture of the diasteromers.

Example 60

Methyl3-[2-(4-(2-carbomethoxy-1-methylethenyl)phenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate

Prepared by analogy to Example 18 by reaction ofN-[2-(4-(2-carbomethoxy-1-methylethyl)phenyl)-1-methyl-ethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanaminewith methyl glyoxylate followed by purification of the base on a silicagel column using chloroform/petroleum ether/ethyl acetate =5:4.5:0.5 aseluant.

Yield: 66% of theory,

    ______________________________________                                        Calculated:                                                                              C 55.41   H 5.05   N 5.62  S 6.43                                  Found:     55.33     5.23     4.96    6.64                                    ______________________________________                                    

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=5.10 ppm (s, 2H) δ=5.23 ppm (s, 1H)δ=5.27 ppm (s, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is a 1:1:1:1mixture of the diasteromers.

Example 61

Methyl3-[2-(4-Hydroxyphenyl)-1-methylethyl]-5-(2-trifluoromethylthiazol-4-yl)-2carboxylate

Prepared by analogy to Example 18 by reaction ofN-[2-(4-hydroxyphenyl)-2-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)ethanaminewith methyl glyoxylate, followed by purification of the base on a silicagel column using chloroform/ethyl acetate =9:1 eluant and precipitationof the hydrochloride with ethereal hydrochloric acid.

Yield: 37% of theory,

Melting point: from 158° C. (decomp.)

    ______________________________________                                        Calculated:                                                                           C 47.74  H 4.45   N 6.19 S 7.08 Cl 7.88                               Found:  47.49    4.72     6.38   7.22   7.98                                  ______________________________________                                    

Example 62

Methyl3-[2-(4-(2-Carbomethoxy-1-methylethenyl)phenyl)-1-methylethyl]-5-(2-methyl-thiazol-4-yl)-2-oxazolidinecarboxylate

Prepared by analogy to Example 18 by reaction ofN-[2-(4-(2-carbomethoxy-1-methylethenyl)phenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanaminewith methyl glyoxylate, followed by purification of the base on a silicagel column using petroleum ether/ethyl acetate =7:3 as eluant.

Yield: 18% of theory, oil,

    ______________________________________                                        Calculated:                                                                              C 62.14   H 6.35   N 6.30  S 7.21                                  Found:     61.90     6.60     6.34    7.03                                    ______________________________________                                    

Example 63

Methyl3-[2-(4-hydroxyphenyl)-1-methylethyl]-5-(2-methyl-thiazol-4-yl)-2-oxazolidinecarboxylate

Prepared by analogy to Example 18 by reaction ofN-[2-(4-hydroxyphenyl)-1-methylethyl]-2-(2-methyl-thiazol-4-yl)ethanaminewith methyl glyoxylate, followed by purification of the base on a silicagel column using ether/petroleum ether =8:2 as eluant.

Yield: 25% of theory, oil,

    ______________________________________                                        Calculated:                                                                              C 59.65   H 6.12   N 7.73  S 8.85                                  Found:     60.00     5.98     7.23    8.97                                    ______________________________________                                    

Example 64

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-6-one

2.1 g (0.0005 mol) ofN-[2-(4-carbomethoxymethoxyphenyl-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamineare dissolved in 70 ml of acetone, and while stirring 5 ml of methylbromoacetate and 5 g of potassium carbonate are added. The mixture isinitially stirred at room temperature for 16 hours then heated underreflux for 4 hours. The inorganic products are removed by filtration,the solvent is removed by distillation, and the resulting residue ispurified on a silica gel column using toluene/ethyl acetate =8.1:1.5 aseluant.

Yield: 0.8 g of oil (35% of theory),

    ______________________________________                                        Calculated:  C 52.39    H 4.62    N 6.11                                      Found:       52.50      4.51      5.85                                        ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.596 ppm (d, 1H) δ=7.686ppm (d, 1H)

According to this, the product is a 50:50 mixture of diastereomers.

Example 65

N-[2-(4-Carboethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholinehydrochloride

0.5 g (0.0012 mol) ofN-[2-(4-carboxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholineis dissolved in 150 ml of chloroform and, while stirring, 2 ml ethanoland 0.25 g of concentrated sulphuric acid are added, and then themixture is heated to reflux with a water trap for one hour. The mixtureis then cooled, ice-water is added, the mixture is made alkaline withammonia and the phases are separated. The aqueous phase is thenextracted again by shaking with chloroform, and the organic phase isdried over sodium sulphate, filtered and evaporated to dryness. Theresulting residue is dissolved in ether, ethereal hydrochloric acid isadded, the mixture is evaporated to dryness, and the residue istriturated with acetone and filtered off with suction.

Yield 0.37 g (63% of theory),

Melting point: 122°-123° C.

    ______________________________________                                        Calculated:  C 50.95    H 5.30    N 5.66                                      Found:       50.85      5.49      5.68                                        ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is a 50:50mixture of the diasteromers.

Example 66

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-5-yl)ethanaminedihydrochloride

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-methyl-thiazol-5-yl)ethanamine with1-(4-carbomethoxymethoxyphenyl)propan-2-one, purification of the base ona silica gel column using ethyl acetate/ethanol =8:2 as eluant and thenprecipitation of the dihydrochloride using ethereal hydrochloric acid.

Yield 32% of theory,

Melting point: 190°-192° C.

    ______________________________________                                        Calculated:  C 49.93    H 5.99    N 6.40                                      Found:       49.43      5.90      6.49                                        ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 50:50 mixture of the diasteromers.

Example 67

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine(Diastereomer B)

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with1-(4-carbomethoxymethoxyphenyl)propan-2-one and sodium cyanoborohydridein methanol (reaction time: 5 hours) followed by purification on asilica gel column using methylene chloride/methanol =20:1. This resultsin a 50:50 diastereomer mixture of the base. This is recrystallised froma mixture of ether/ethyl acetate =65:10. The mother liquor resultingfrom this is mixed with ethereal hydrochloric acid, and the mixture isevaporated to dryness. The residue resulting from this is recrystallisedfrom a mixture of ether/ethyl acetate/methanol =100:60:1. The motherliquor obtained after the crystals have been removed by filtration isevaporated to dryness, and the base is liberated by shaking with alkaliand methylene chloride and purified on a silica gel column usingmethylene chloride/methanol =20:1 as eluant. This results indiastereomer B as an oil approximately 92-94% pure.

Yield: 4% of theory,

    ______________________________________                                        Calculated:  C 54.66    H 5.06    N 6.70                                      Found:       54.43      5.13      6.88                                        ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.56 ppm (s, 1H)

Example 68

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine(Diastereomer A)

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with1-(4-carbomethoxymethoxyphenyl)propan-2-one and sodium cyanoborohydridein methanol=(reaction time: 5 hours) followed by purification on asilica gel column using methylene chloride/methanol 20:1. This resultsin an approximately 50:50 diastereomer mixture of the base. This isrecrystallised from a mixture of ether/ethyl acetate=65:10, and twicemore from ethyl acetate. This results in diastereomer A in 98-99%purity.

Yield: 14% of theory,

Melting point: 104-105° C.

    ______________________________________                                        Calculated:  C 51.66    H 5.06    N 6.70                                      Found:       51.90      4.82      6.82                                        ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.59 ppm (s, 1H)

Example 69

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine(Diastereomer A)

Prepared by analogy to Example 16 by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine(diastereomer A) in methanol with 1N sodium hydroxide solution. Afterthe mixture has been neutralised with 1N hydrochloric acid it isextracted by shaking with methylene chloride; the extract is evaporatedto dryness, and the remaining residue is triturated with petroleum etherand is filtered off with suction.

Yield: 96% of theory,

Melting point: from 70° C. (sintering)

    ______________________________________                                        Calculated:  C 53.01    H 4.92    N 6.51                                      Found:       53.15      4.97      6.53                                        ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.757 ppm (s, 1H)

Example 70

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine(Diastereomer B)

Prepared by analogy to Example 16 by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine(diastereomer B) in methanol with 1N sodium hydroxide solution. Afterthe mixture has been neutralised with 1N hydrochloric acid it isextracted by shaking with methylene chloride, the extract is evaporatedto dryness, and the remaining residue is triturated with petroleum etherand is filtered off with suction.

Yield: 88% of theory,

Melting point: from 70° C. (sintering)

    ______________________________________                                        Calculated:  C 53.01    H 4.92    N 6.51                                      Found:       53.19      5.19      6.48                                        ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.786 ppm (s, 1H)

According to this the compound still contains about 6-7% of diastereomerA.

Example 71

N-[2-(4-(2Hydroxyethoxy)phenyl)-1methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine(Diastereomer A)

1 g (0.0022 Mol) ofN-[2-(4-carbomethoxymethoxy-phenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-5-one(diastereomer A) is dissolved in 6 ml of absolute tetrahydrofuran. Atroom temperature 15 ml (0.015 Mol) of a one molar solution of diboranein tetrahydrofuran is added dropwise within 15-20 minutes. During thisthe solution heated up to about 35°-40° C. After 30 minutes the mixtureis evaporated to dryness and the remaining residue is dissolved in 40 mlof methanol and 2 ml of concentrated hydrochloric acid, and the mixtureis left to stand for 30 minutes. While cooling in ice, the mixture ismade alkaline with ammonia and is extracted several times by shakingwith methylene chloride. The organic phase is dried over sodium sulphateand the base is purified on a silica gel column using toluene/ethylacetate =7.5:2.5 as eluant.

Yield: 0.28 g (31% of theory),

Melting point: 76°-78° C.

    ______________________________________                                        Calculated:  C 54.79    H 5.57    N 6.73                                      Found:       54.90      5.71      6.54                                        ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.614 ppm (s, 1H)

Example 72

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine(Diastereomer A)

Prepared by analogy to Example 16 by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2(2-trifluoromethyl-thiazol-4-yl)ethanamine(diastereomer A) in methanol with 1N sodium hydroxide solution. Afterthe mixture has been neutralised with 1N hydrochloric acid it isextracted by shaking with methylene chloride, the extract is evaporatedto dryness, and the remaining residue is triturated with petroleum etherand filtered off with suction.

Yield: 89% of theory,

Melting point: 119°-121° C.

    ______________________________________                                        Calculated:  C 50.49    H 4.74    N 6.93                                      Found:       50.62      4.69      6.90                                        ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.771 ppm (s, 1H)

Example 73

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2(hydroxy-2-(2trifluoromethyl-thiazol-4-yl)ethanamine

Prepared by analogy to Example 16 by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanaminein methanol with 1N sodium hydroxide solution. After the mixture hasbeen neutralised with 1N hydrochloric acid it is evaporated to dryness,treated with 10 ml of ethanol, and the inorganic residues are removed byfiltration. The ethanol phase is diluted with 60 ml of methylenechloride and again filtered. The mother liquor is evaporated to dryness,and the residue is triturated with ether and filtered off with suction.

Yield: 90% of theory,

Melting point: 83°-85° C.

    ______________________________________                                        Calculated:  C 50.88    H 5.17    N 6.25                                      Found:       50.70      5.44      6.11                                        ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 60:40 diastereomer mixture.

Example 74

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine(Diastereomer A)

a)N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4yl)morpholin-5-one(Diastereomer A)

1.2 g (0.0029 mol) ofN-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol)-4-ylethanamine (diastereomer A) are dissolved in 12 ml of methylenechloride, and the solution is cooled to 12° C. and 0.4 ml (0.0029 mol)of triethylamine is added. While stirring, 0.22 ml (0.0029 mol) ofchloroacetyl chloride is added dropwise. The temperature rises to 24° C.during this. After 30 minutes the organic phase is extracted by shakingwith water, dried over sodium sulphate and evaporated to dryness. Theoil which results from this is taken up in 12 ml of dimethylformamideand, while stirring, reacted at 22°-24° C. with 130 mg of 50% sodiumhydride dispersion in oil. After one hour a further 90 mg of 50% sodiumhydride dispersion are added to complete the reaction. After a total of1.5 hours the mixture is neutralised with ethereal hydrochloric acid,and 100 ml of methylene chloride are added. The organic phase isextracted by shaking with water, and the latter is extracted a further 2x with methylene chloride. After the organic phases have been dried oversodium sulphate they are evaporated to dryness. The resulting oil ispurified on a silica gel column using toluene/ethyl acetate =6:4 aseluant.

Yield 1.2 g (90% of theory).

b)N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine(Diastereomer A)

1.2 g (0.0026 mol) ofN-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-5-one(diastereomer A) are dissolved in 10 ml of absolute tetrahydrofuran at22° C. Three portions of 2.8 ml (0.0028 mol) of a 1 molar solution ofdiborane in tetrahydrofuran are added dropwise to this solution atintervals of 30 minutes in each instance. The mixture is evaporated todryness after 1.5 hours. The resulting residue is taken up in 80 ml ofmethanol and the solution is left to stand at room temperature for 16hours. It is again evaporated to dryness and the resulting residue istaken up in methylene chloride, and the organic phase is extracted witha cold aqueous ammonia solution. The methylene chloride phase isextracted 2× with water, and the organic phase is dried over sodiumsulphate and concentrated. The resulting residue is purified on a silicagel column using toluene/ethyl acetate =8:2 as eluant. This results in acolourless oil.

Yield: 0.8 g (69.3% of theory),

    ______________________________________                                        Calculated:  C 54.04    H 5.22    N 6.30                                      Found:       54.20      5.53      6.41                                        ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=4.807 ppm (dd, 1H)

Example 75

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine(Diastereomer B)

a)N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-5-one(Diastereomer B)

Prepared by analogy to Example 74a by reaction ofN-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine(diastereomer B), chloroacetyl chloride and sodium hydride, andpurification of the base on a silica gel column using toluene/ethylacetate =6:4 as eluant.

Yield: 71% of theory.

b)N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine(Diastereomer B)

Prepared by analogy to Example 74b by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-5-one(diastereomer B) with diborane in tetrahydrofuran, followed bypurification of the base on a silica gel column using toluene/ethylacetate =8:2 as eluant.

Yield: 53% of theory,

    ______________________________________                                        Calculated:  C 54.04    H 5.22    N 6.20                                      Found:       54.31      5.35      6.22                                        ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=4.829 ppm (dd, 1H)

Example 76

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-(carboethoxymethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

0.21 g (0.005 mol) ofN-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine is dissolved in 10 ml of butan-2-one, and 0.5 ml of ethylbromoacetate and 0.5 g of potassium carbonate are added, and the mixtureis stirred at room temperature for 16 hours. The inorganic products areremoved by filtration, and the solvent is removed by distillation. Theremaining oil is purified on a silica gel column using toluene/ethylacetate =85:15 as eluant. A colourless oil is obtained.

Yield: 0.14 g (56% of theory),

    ______________________________________                                        Calculated:  C 52.47    H 5.41    N 5.56                                      Found:       52.71      5.42      5.57                                        ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 50:50 mixture of the diastereomers.

Example 77

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-N-(carboxymethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

1.4 g (0.0031 mol) ofN-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-6-oneare dissolved in 10 ml of methanol. 3 ml (0.003 mol) of 1N sodiumhydroxide solution are added to this stirred solution at roomtemperature. After 5 minutes 15 ml of ice-water are added, and themixture is neutralised with 3 ml of 1N hydrochloric acid. The aqueousphase is extracted by shaking 3× with methylene chloride. The organicphase is dried over sodium sulphate, filtered and evaporated to dryness.The resulting residue is purified on a silica gel column using methylenechloride methanol =20:1 as eluant. This results, after concentration, incolourless crystals.

Yield: 0.29 g (21% of theory),

Melting point: 128° C.

    ______________________________________                                        Calculated:  C 50.41    H 4.86    N 5.88                                      Found:       50.19      4.89      5.74                                        ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 50:50 mixture of the diastereomers.

Example 78

N-[2-(4-(2-(1-Piperidino)ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with1-(4-(2-(1-piperidino)ethoxy)phenyl)propan-2-one followed bypurification on a silica gel column using methanol as eluant.

Yield: 13% of theory,

Melting point: 128° C.

    ______________________________________                                        Calculated:                                                                              C 65.48  H 8.24   N 10.41  S 7.94                                  Found:     65.39    8.17     10.29    7.79                                    ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃): δ=4.75 (dd, CH--OH) δ=4.70 (dd,CH--OH)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 1:1 mixture of the diastereomers.

Example 79

N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with1-[4-(2-hydroxyethoxy)phenyl)propan-2-one followed by purification on asilica gel column using methylene chloride/methanol =9:1 as eluant.

Yield: 61% of theory,

    ______________________________________                                        Calculated:                                                                              C 60.69   H 7.19   N 8.33  S 9.53                                  Found:     60.59     7.13     8.25    9.47                                    ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃): δ=4.78 (dd, CH--OH) δ=4.83 (dd,CH--OH)

According to the ¹ H-NMR spectrum (400 MHz) the product is approximately1:1 mixture of the diastereomers.

Example 80

N-[2-(4-Carbomethoxyphenyl)-1-methyylethyl]-2-hydroxy-2-(2-dimethylamino-thiazol-4-yl)ethanamine

5 g of 2-(N,N-dimethylamino)-4-bromoacetyl-thiazole in 250 ml of acetoneare heated to reflux with 10 g of potassium hydrogen carbonate and 9.5 gof 2-(4-carbomethoxyphenyl)-1-methylethylamine-hydrochloride for 3hours. After the reaction mixture has been cooled the inorganic productsare removed by filtration, and the filtrate is concentrated in a rotaryevaporator. The resulting oil residue is taken up in 150 ml of absolutemethanol and, at 0°-5° C., 1.75 g of sodium borohydride are added insmall portions. The mixture is then stirred at 0°-5° C. for one hour andat room temperature for 24 hours. Then ice-water are added to thereaction mixture, and it is acidified with concentrated hydrochloricacid, made alkaline with ammonia, while cooling in ice, and extractedwith methylene chloride. The extract is dried over sodium sulphate,concentrated and purified on a silica gel column using ethylacetate/methanol =8:2 as eluant.

Yield: 0.5 g (6.8% of theory),

    ______________________________________                                        Calculated:                                                                              C 59.43  H 6.93   N 11.56  S 8.82                                  Found:     59.38    7.07     11.39    9.04                                    ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=6.39 ppm (s, 1H) δ=6.37ppm (s, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 2:1 mixture of the diastereomers.

Example 81

N-[2-(Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-methyl-thiazol-4-yl)morpholine

Prepared ny analogy to Example 13 by reaction of2-(2-methyl-thiazol-4-yl)morpholine with1-(4-carbomethoxymethoxyphenyl)propan-2-one followed by purification ona silica gel column using toluene/ethyl acetate =6:4 as eluant.

Yield: 22% of theory,

    ______________________________________                                        Calculated:                                                                              C 61.52   H 6.71   N 7.17  S 8.21                                  Found:     61.68     6.89     6.98    8.32                                    ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=2.71 ppm (s, 1H) δ=2.72ppm (s, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 1:1 mixture of the diastereomers.

Example 82

N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with1-(4-(2-hydroxyethoxy)phenyl)propan-2-one followed by purification on asilica gel column using ethyl acetate/methanol =9:1 as eluant.

Yield: 27.6% of theory,

    ______________________________________                                        Calculated:                                                                              C 52.30   H 5.42   N 7.18  S 8.21                                  Found:     52.19     5.57     7.13    8.40                                    ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.60 ppm (s, 1H) δ=7.57ppm (s, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 1:1 mixture of the diastereomers.

Example 83

N-[2-(4-(2-Methylaminoethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

1.2 ml of borane/dimethyl sulfide complex are added to a solution of0.38 g ofN-[2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanaminein 20 ml of absolute tetrahydrofuran, and the mixture is heated toreflux for three hours. The 4 ml of methanol are cautiously addeddropwise to the reaction mixture, and the mixture is heated to refluxfor one hour. After cooling to room temperature, ethereal hydrochloricacid is added. The resulting solution is evaporated, the resultingresidue is taken up in 15 ml of water, and the solution is made alkalinewith concentrated ammonia and extracted several times with methylenechloride. The combined extracts are dried with sodium sulphate,evaporated and purified on a silica gel column using methylenechloride/methanol =8:2 as eluant.

Yield: 0.06 g (13.6% of theory),

    ______________________________________                                        Calculated:  C 53.59   H 6.00     N 10.42                                     Found:       53.40     6.19       10.20                                       ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.60 ppm (s, 1H) δ=7.57ppm (s, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 1:1 mixture of the diastereomers.

Example 84

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

Prepared by analogy to Example 32 by reaction of2-trifluoromethyl-4-bromoacetyl-thiazole withN-(2-hydroxyethyl)-2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethylamineand potassium hydrogen carbonate in acetone at room temperature,followed by reduction with sodium borohydride in trifluoroacetic acid.The resulting crude product is purified on a silica gel column usingtoluene/ethyl acetate =2:8 as eluant.

Yield: 47.4% of theory,

Melting point: 96°-98° C.

    ______________________________________                                        Calculated:                                                                              C 54.17   H 5.46   N 9.48  S 7.23                                  Found:     53.99     5.42     9.38    7.39                                    ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.61 ppm (s, 1H) δ=7.59ppm (s, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 1:1 mixture of the diastereomers.

Example 85

N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2-(2-methyl-thiazol-4-yl)morpholine

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-methyl-thiazol-4-yl)morpholine with1-[4-(2-hydroxyethyoxy)phenyl]propan-2-one followed by purification on asilica gel column using methylene chloride as eluant.

Yield: 42% of theory,

    ______________________________________                                        Calculated:  C 63.13    H 6.97    N 7.75                                      Found:       63.03      6.95      7.68                                        ______________________________________                                    

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=7.14 ppm (s, 1H) δ=7.13 ppm (s, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 2:3 mixture of the diastereomers.

Example 86

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-(2-methyl-thiazol-4-yl)morpholine

Prepared by analogy to Example 13 by reaction of2-(2-methyl-thiazol-4-yl)morpholine with1-[4-carbomethoxyphenyl]propan-2-one followed by purification on asilica gel column using methylene chloride/ethylacetate/methanol/ammonia =4:4:2:1 as eluant.

Yield: 28% of theory,

    ______________________________________                                        Calculated:                                                                              C 60.62   H 6.42   N 7.44  S 8.52                                  Found:     60.58     6.40     7.40    8.50                                    ______________________________________                                    

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=7.13 ppm (s, 1H) δ=7.14 ppm (s, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 1:1 mixture of the diastereomers.

Example 87

N-[2-(4-(6-Hydroxyhexoxy)phenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

Prepared by analogy to Example 32 by reaction ofN-(2-hydroxyethyl)-2-(4-(6-hydroxyhexoxy)phenyl)-1-methylethylamine with2-trifluoromethyl-4-bromoacetyl-thiazole and potassium hydrogencarbonate in acetone at room temperature, followed by reduction withsodium borohydride in trifluoroacetic acid. The resulting crude productis purified on a silica gel column using toluene/ethyl acetate =6:4 aseluant.

Yield: 10.8% of theory,

    ______________________________________                                        Calculated:                                                                              C 58.46   H 6.61   N 5.93  S 6.78                                  Found:     58.57     6.49     5.79    6.91                                    ______________________________________                                    

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=7.61 ppm (s, 1H) δ=7.57 ppm (s, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 1:1 mixture of the diastereomers.

Example 88

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-(2-methyl-thiazol-4-yl)morpholine

Prepared by analogy to Example 13 by reaction of2-(2-methyl-thiazol-4-yl)morpholine with1-(4-methylaminocarbonylmethoxyphenyl)propan-2-one followed bypurification on a silica gel column using ethyl acetate as eluant.

Yield: 22.3% of theory,

    ______________________________________                                        Calculated:                                                                              C 61.67  H 6.99   N 10.79  S 8.23                                  Found:     61.70    6.97     10.67    8.42                                    ______________________________________                                    

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=2.72 ppm (s, 3H) δ=2.71 ppm (s, 3H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 1:1 mixture of the diastereomers.

Example 89

N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

Prepared by analogy to Example 24 by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholinewith ammonia followed by purification on a silica gel column using ethylacetate/toluene =8.2 as eluant.

Yield: 51.7% of theory,

    ______________________________________                                        Calculated:                                                                              C 53.14   H 5.16   N 9,78  S 7.47                                  Found:     53.26     5.34     9.63    7.59                                    ______________________________________                                    

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=7.71 ppm (s, 1H) δ=7.69 ppm (s, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 1:1 mixture of the diastereomers.

Example 90

N-[2-(4-(2-Methylaminoethoxy)phenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

Prepared by analogy to Example 83 by reaction ofN-[2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholinewith borane dimethylsulfide complex followed by purification on a silicagel column using ethyl acetate/methanol (8:2) as eluant.

Yield: 26% of theory,

    ______________________________________                                        Calculated:  C 55.93    H 6.10    N 9.78                                      Found:       56.08      6.21      9.65                                        ______________________________________                                    

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=7.63 ppm (s, 1H) δ=7.59 ppm (s, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 1:1 mixture of the diastereomers.

Example 91

N-[2-(4-(6-Hydroxyhexoxy)phenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

Prepared by analogy to Example 13 by reaction of2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with1-(4-(6-hydroxyhexoxyphenyl)propan-2-one followed by purification on asilica gel column using ethyl acetate/methanol (9.5:0.5) as eluant.

Yield: 17.4% of theory,

    ______________________________________                                        Calculated:                                                                              C 56.49   H 6.55   N 6.27  S 7.18                                  Found:     56.32     6.47     6.34    7.28                                    ______________________________________                                    

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=7.59 ppm (s, 1H) δ=7.55 ppm (s, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 1:1 mixture of the diastereomers.

Example 92

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifuoromethyl-5-methyl-thiazol-4-yl)morpholine

Prepared by analogy to Example 32 by reaction of 4.2 g (0.0146 mol) of2-trifluoromethyl-5-methyl-4-bromoacetyl-thiazole with 8 g (0.03 mol) ofN-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine inmethylene chloride by stirring at room temperature for 20 hours andheating under reflux for 2 hours. The reduction is carried out in 28 mlof trifluoroacetic acid using 2.4 g (0.02 mol) of triethylsilane. Thecrude product is purified on a silica gel column using toluene/ethylacetate =7:3 as eluant.

Yield: 1.7 g (28% of theory),

    ______________________________________                                        Calculated:                                                                              C 55.01   H 5.49   N 6.10  S 6.99                                  Found:     55.20     5.60     6.30    7.20                                    ______________________________________                                    

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=4.775 ppm (t, 1H) 67 =4.810 ppm (t,1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 3:2 mixture of the diastereomers.

Example 93

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-acetamino-thiazol-4-yl)morpholine

Prepared by analogy to Example 32 by reaction of 2.23 g (0.0085 mol) of2-acetylamino-4-bromoacetylthiazole with 2.26 g of (0.0085 mol) ofN-(2-hydroxy-ethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamineand 0.86 g (0.0085 mol) of triethylamine in 30 ml of methylene chlorideand 30 ml of methanol for 20 hours at room temperature. The reduction iscarried out in 9 ml of trifluoroacetic acid using 1.48 g (0.0128 mol) oftriethylsilane. The crude product is purified on a silica gel columnusing ethyl acetate/methanol =9:1 as eluant.

Yield: 1 g (27% of theory),

Melting point: 65°-70° C.

    ______________________________________                                        Calculated:                                                                              C 58.18   H 6.27   N 9.69  S 7.33                                  Found:     57.90     6.40     9.49    7.48                                    ______________________________________                                    

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=6.875 ppm (d, 1H) δ=6.850 ppm (d,1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 2:1 mixture of the diastereomers.

Example 94

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-oxazol-4-yl)ethanaminedihydrochloride

Prepared by analogy to Example 13 by reaction of 0.7 g (0.005 mol) of2-hydroxy-2-(2-methyl-oxazol-4-yl)-ethanamine and 1.1 g (0.005 mol) of1-(4-carbomethoxymethoxyphenyl)propan-2-one in 40 ml absolute methanolwith 0.3 g (0.005 mol) of acetic acid and 0.32 g (0.005 mol) of sodiumcyanoborohydride. The crude product is purified on a silica gel columnusing ethyl acetate/methanol =9:1 as eluant, and the dihydrochloride isprepared by precipitation with ethereal hydrochloric acid.

Yield: 0.6 g (28% of theory),

Melting point: 160° C. sintering, above 168° C. decomp.

    ______________________________________                                        Calculated:                                                                              C 51.30   H 6.21   N 6.64  S 16.84                                 Found:     51.50     6.10     6.76    16.57                                   ______________________________________                                    

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=7.49 ppm (d, 1H) δ=7.51 ppm (d, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 50:50 mixture of the diastereomers.

Example 95

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-chloro-thiazol-4-yl)morpholine

Prepared by analogy to Example 32 by reaction of 5 g (0.0208 mol) of2-chloro-4-bromoacetyl-thiazole with 5.6 g (0.021 mol) ofN-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine in200 ml of acetone and 6.3 g (0.063 mol) of potassium hydrogen carbonateover 20 hours at room temperature. The reduction is carried out in 41 mlof trifluoroacetic acid using 3.5 g (0.029 mol) of triethylsilane for 24hours. The crude product is purified on a silica gel column usingmethylene chloride/methanol =20:1 as eluant.

Yield: 1.2 g (16% of theory),

    ______________________________________                                        Calculated:  C 55.53    H 5.64    N 6.81                                      Found:       55.41      5.70      6.57                                        ______________________________________                                    

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=7.21 ppm (d, 1H) δ=7.22 ppm (d, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 2:3 mixture of the diastereomers.

Example 96

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-(2-amino-thiazol-4-yl)morpholinedichloride

1.6 g (0.0037 mol) ofN-[2-(4-carbomethoxymethoxyphenyl)1-methylethyl]-2-(2-acetamino-thiazol-4-yl)morpholinein 100 ml of 18% strength hydrochloric acid are heated to reflux undernitrogen for 48 hours. 1.5 g of active charcoal are added to thereaction solution which is thoroughly stirred and filtered. The solutionis then concentrated, and the product is dried in vacuo over potassiumhydroxide.

Yield: 1.66 g (100% of theory),

    ______________________________________                                        Calculated:                                                                           C 47.99  H 9.32   N 8.32 S 7.11 Cl 15.76                              Found:  48.20    9.45     8.99   7.18   15.78                                 ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is a 2:1 mixtureof the diastereomers.

Example 97

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-(2-chloro-thiazol-4-yl)morpholine

0.55 g (0.0013 mol) ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-chloro-thiazole-4-yl)morpholineare stirred in 4 ml of methanol and 4 ml of 1N sodium hydroxide solutionat room temperature for 10 minutes. The mixture is then neutralised with4 ml of 1N hydrochloric acid, and the product is obtained by extractionwith methylene chloride.

Yield: 0.52 g (100% of theory),

Melting point: 80°-90° C. (decomp.)

    ______________________________________                                        Calculated:                                                                              C 54.47   H 5.33   N 7.05  Cl 8.93                                 Found:     54.40     5.42     7.00    8.90                                    ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is a 2:3 mixtureof the diastereomers.

Example 98

N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2-(2-chloro-thiazol-4-yl)morpholine

Prepared by analogy to Example 71 by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-chloro-thiazol-4-yl)morpholinewith borane/tetrahydrofuran complex (1 molar solution intetrahydrofuran) for 60 hours.

Yield: 35% of theory,

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=7.209 ppm (d, 1H) δ=7.228 ppm (d,1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is a 2:3 mixtureof the diastereomers.

Example 99

N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanamine

Prepared by analogy to Example 71 by reaction ofN-[2-(4-carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanaminewith borane/tetrahydrofuran complex (1 molar solution intetrahydrofuran) for 24 hours.

Yield: 20% of theory,

¹ H-NMR spectrum (CDCl₃ /CD₃ OD): δ=7.195 ppm (d, 1H) δ=7.22 ppm (d, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is a 1:1 mixtureof the diastereomers.

Example 100

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanamine

Prepared by analogy to Example 97 by reaction ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanaminewith 1N sodium hydroxide solution in methanol

Yield: 0.19 g (100% of theory),

Melting point: 58°-63° C.

    ______________________________________                                        Calculated:  C 51.82    H 5.16    N 7.55                                      Found:       51.75      5.22      7.58                                        ______________________________________                                    

Example 101

N-[2-(4-(2-Hydroxyethoxy)-phenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazole-4-yl)ethanamine

Prepared by analogy to Example 71 by reaction ofN-[2-(4-carboxymethoxyphenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanaminein tetrahydrofuran with diborane in tetrahydrofuran and purification ofthe base on a silica gel column using an ethyl acetate/methanol =20:1 aseluant.

Yield: 54% of theory, oil,

    ______________________________________                                        Calculated:  C 52.52    H 5.80    N 6.45                                      Found:       52.19      5.72      6.39                                        ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.828 ppm (s, 1H) δ=7.839ppm (s, 1H)

The product is a 60:40 mixture of the diastereomers.

Example 102

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-piperidino-thiazol-4-yl)morpholine

Prepared by analogy to Example 32 by reaction of 2.9 g (0.1 mol) of2-piperidino-4-bromoacetyl-thiazol with 3.2 g (0.012 mol) ofN-(2-Hydroxyethyl)-2-(4-carbomethoxyphenyl)-1-methylethylamine in 200 mlacetone in the presence of 3 g (0.03 mol) of potassium hydrogencarbonate followed by a reduction in 60 ml of trifluoroacetic acid with2.9 g (0.076 mol) of sodium borohydride for 24 hours. The substance ispurified on a silica gel column using ethyl acetate as eluant, a yellowoil being obtained.

Yield: 0.8 g (17% of theory),

    ______________________________________                                        Calculated:                                                                              C 62.71   H 7.23   N 9.14  S 6.97                                  Found:     62.50     7.33     9.40    6.92                                    ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 33:66 mixture of the diastereomers: δ=6.33 ppm (d, 1H)δ=6.44 ppm (d, 1H)

Example 103

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-piperidino-thiazol-4-yl)ethanaminehydrochloride

Prepared by analogy to Example 3 by reaction of2-piperidino-4-bromoacetyl-thiazole with2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine followed byreduction. The compound is purified on a silica gel column using ethylacetate/methanol =9:1 as eluant, and the base is converted into thehydrochloride using ethereal hydrochloric acid.

Yield: 13% of theory,

Melting point: above 100° C. decomp.

    ______________________________________                                        Calculated:                                                                           C 52.16  H 6.56   N 8.29 S 6.32 Cl 14.01                              Found:  51.80    6.83     8.17   6.48   13.72                                 ______________________________________                                    

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 50:50 mixture of the diastereomers.

Example 104

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

0.54 g (0.030 mol) of 2-(2-trifluoromethyl-thiazol-4-yl)ethylene oxideis dissolved in 5 ml of ethanol, and the solution is added dropwisewithin 10 minutes to a boiling solution of 0.58 g (0.0030 mol) of2-(4-carbomethoxyphenyl)-1-methylethylamine in 13 ml ethanol. Themixture is then boiled under reflux for 5 hours, the solvent is removedby distillation, and the base is purified on a silica gel column usingmethylene chloride/methanol =20:1 as eluant.

Yield 0.45 g (38% of theory),

    ______________________________________                                        Calculated:  C 52.57    H 4.93    N 7.21                                      Found:       52.34      5.11      7.11                                        ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.58 ppm (s, 1H) δ=7.61ppm (s, 1H)

The product is an approximately 50:50 mixture of the diastereomers.

Example 105

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine

Prepared by analogy to Example 104 by reaction of2-(2-trifluoromethyl-thiazol-4-yl)ethylene oxide with2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine and dimethylsulfoxide at 90° C. for 16 hours. The base is obtained by extraction byshaking with ether and purification on a silica gel column usingmethylene chloride/methanol 20:1 as eluant.

Yield: 24% of theory,

    ______________________________________                                        Calculated:  C 51.66    H 5.06    N 6.70                                      Found:       51.50      4.99      6.71                                        ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.57 ppm (d, 1H) δ=7.61ppm (d, 1H)

The product is an approximately 50:50 mixture of the diastereomers.

Example 106

N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-N-(2-hydroxy-ethyl)-2-hydroxy-2-(2-chloro-thiazol-4-yl)ethanaminePrepared by analogy to Example 30 by reaction of2-chloro-4-bromoacetyl-thiazole withN-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylaminefollowed by reduction in methanol with sodium borohydride at roomtemperature. The crude product is purified on a silica gel column usingchloroform/ethyl acetate/methanol =10:9:1 as eluant.

Yield: 15% of theory,

    ______________________________________                                        Calculated:                                                                           C 53.92  H 6.29   N 6.99 S 8.00 Cl 8.84                               Found:  53.68    6.30     6.57   7.61   8.72                                  ______________________________________                                    

¹ H-NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.22 ppm (d, 1H) δ=7.11ppm (d, 1H)

According to the ¹ H-NMR spectrum (400 MHz) the product is anapproximately 1:1 mixture of the diastereomers.

Example 107

N-[2-(4-Methoxycarbonylmethoxyphenyl)-1-methylethyl]-2-methoxy-2-(2-methyl-thiazol-4-yl)ethanaminedihydrochloride x 1.5 H₂ O

Prepared by analogy to Example 13 by reaction of2-methoxy-2-(2-methyl-thiazol-4-yl)ethanamine with1-(4-methoxycarbonylmethoxyphenyl)propan-2-one followed by purificationof the base by column chromatography on silica gel usingchloroform/methanol =10/1 as eluant.

Yield: 58% of theory,

¹ H-NMR spectrum (400 MHz) (CDCl₃): δ=4.40 ppm (dd, ═CH-OMe) δ=4.44 ppm(dd, ═CH-OMe)

According to the ¹ H-NMR spectrum the product is an approximately 50:50mixture of the diastereomers. The oily base is converted into afoam-like dihydrochloride using hydrogen chloride/methanol.

Melting point: 60°-80° C.

    __________________________________________________________________________    Calculated:                                                                            C 47.69                                                                             H 6.53                                                                              N 5.86                                                                              S 6.70                                                                              Cl                                                                              14.82                                      (× 1.5 H.sub.2 O)                                                       Found:     47.77 6.68  6.01  7.07  14.98                                      __________________________________________________________________________

Example I

Coated tablet containing 10 mg ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethanamine

Composition:

1 Coated tablet contains:

    ______________________________________                                        (1) Active substance                                                                            10.0 mg                                                     (2) Lactose       69.0 mg                                                     (3) Maize starch  35.0 mg                                                     (4) Polyvinylpyrrolidone                                                                         5.0 mg                                                     (5) Magnesium stearate                                                                           1.0 mg                                                                       120.0 mg                                                    ______________________________________                                    

Preparation:

(1)+(2)+(3) are mixed and moistened with (4) in an aqueous solution. Themoist composition is beaten through a screen of mesh width 1.6 mm and isdried in a circulating drier at 45° C. The dry granules are passedthrough a screen of mesh with 1 mm and mixed with (5). The finishedmixture is compressed to form tablet cores.

Core weight: 120.0 mg

Diameter: 7.0 mm

Radius of curvature: 6.0 mm

The tablet cores which have been prepared in this way are coated inknown manner with a layer essentially composed of sugar and talc. Thislayer can also contain colouring extracts. The finished coated tabletsare polished with wax.

Weight of coated tablet: 180.0 mg

Example II

Coated tablet containing 50 mg ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethanamine

Composition:

1 Coated tablet contains:

    ______________________________________                                        (1) Active substance                                                                            50.0 mg                                                     (2) Lactose       10.8 mg                                                     (3) Maize starch  50.0 mg                                                     (4) Polyvinylpyrrolidone                                                                         8.0 mg                                                     (5) Magnesium stearate                                                                           1.2 mg                                                                       220.0 mg                                                    ______________________________________                                    

Preparation:

The preparation is carried out by analogy to Example I.

Core weight: 220.0 mg

Diameter: 9.0 mm

Radius of curvature: 8.0 mm

Weight of coated tablet: 300.0 mg

Example III

Tablets containing 150 mg ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl[-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethanamine

Composition:

1 tablet contains:

    ______________________________________                                        (1) Active substance                                                                              150.0 mg                                                  (2) Lactose         86.0 mg                                                   (3) Maize starch    50.8 mg                                                   (4) Microcrystalline cellulose                                                                    25.0 mg                                                   (5) Polyvinylpyrrolidone                                                                           7.0 mg                                                   (6) Magnesium stearate                                                                             1.2 mg                                                                       320.0 mg                                                  ______________________________________                                    

Preparation:

(1)+(2)+(3)+(4)+(5) are mixed and moistened with water. The moistcomposition is beaten through a screen of mesh width 1.6 mm and is driedat 45° C. The dry granules are passed once more through the same screen,and are mixed with (6). Tablets are compressed from the finishedmixture.

Tablet weight: 320.0 mg

Diameter: 10.0 mm

The tablets are provided with a dividing groove to allow them to behalved.

Example IV

Hard gelatine capsules containing 100 mg ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethanamine

Composition:

1 Capsule contains:

Capsule shell: Size 3 hard gelatine capsules

    ______________________________________                                        Capsule contents:                                                             ______________________________________                                        (1) Active substance                                                                              100.0 mg                                                  (2) Lactose × 1H.sub.2 O                                                                    38.0 mg                                                   (3) Maize starch (dried)                                                                          60.0 mg                                                   (4) Magnesium stearate                                                                             2.0 mg                                                   Weight of capsule contents:                                                                       200.0 mg                                                  (5) Distilled water q.s.                                                      ______________________________________                                    

Preparation:

An approximately 10% solution in distilled water is prepared with asmall portion of the lactose (granulating liquid). The active substance,the remaining lactose and the maize starch are mixed and thoroughlymoistened with the granulating liquid. The composition is screened,dried and, after another screening is homogeneously mixed with magnesiumsterate. The fine-grained granules are dispensed into capsules in asuitable machine.

Example V

Hard gelatine capsules containing 200 mg ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethanamine

Composition:

1 Capsule contains:

Capsule shell: Size 1 hard gelatine capsules

    ______________________________________                                        Capsule contents:                                                             ______________________________________                                        (1) Active substance                                                                              200.0 mg                                                  (2) Lactose × 1H.sub.2 O                                                                    47.0 mg                                                   (3) Maize starch (dried)                                                                          70.0 mg                                                   (4) Magnesium stearate                                                                             3.0 mg                                                   Weight of capsule contents:                                                                       320.0 mg                                                  (5) Distilled water q.s.                                                      ______________________________________                                    

Preparation:

An approximately 10% solution in distilled water is prepared with asmall portion of the lactose (granulating liquid). The active substance,the remaining lactose and the maize starch are mixed and thoroughlymoistened with the granulating liquid. The composition is screened,dried and, after another screening is homogeneously mixed with magnesiumsterate. The fine-grained granules are dispensed into capsules in asuitable machine.

It has also been found that the new 2-hydroxy-morpholines of generalformula ##STR29## and the optical isomers, diastereomers and acidaddition salts thereof, particularly the physiologically acceptable acidaddition salts thereof for pharmaceutical use, have valuablepharmacological properties, namely a superior effect on metabolism, andpreferably a superior effect of lowering blood sugar and reducing bodyfat, and lowering the atherogenic lipoproteins VLDL and LDL.

In general formula I above

M represents an n-alkylene group containing 2 or 3 carbon atomsoptionally mono- or disubstituted by methyl or ethyl groups,

R₂₁ represents a thiazolyl group optionally substituted by a halogenatom or by a trifluoromethyl or alkyl group, a phenyl group optionallysubstituted by one or two halogen atoms or by a trifluoromethyl, cyano,alkyl or alkoxy group, a phenyl group substituted by a halogen atom andby an alkyl or alkoxy group, a phenyl group substituted by an alkylgroup and by an alkoxy group, or an aminophenyl group which issubstituted by one or two halogen atoms or by a cyano group or by ahalogen atom and a cyano group,

R₂₂ represents a hydrogen atom or a thiazolyl group optionallysubstituted by a halogen atom or by a trifluoromethyl or alkyl group and

R₂₃ represents a hydroxy, alkoxy, carboxy, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, analkoxy group containing 1 to 6 carbon atoms which is substituted in theend position by a carboxy, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl or dialkylaminocarbonyl group, an alkoxy groupcontaining 2 to 7 carbon atoms substituted in the end position by ahydroxy, alkoxy, phenylalkoxy, amino, alkylamino, dialkylamino,pyrrolidino, piperidino or hexamethyleneimino group, or an ethenylenegroup optionally substituted by an alkyl group and substituted in theend position by a carboxy, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl or dialkylaminocarbonyl group,

whilst the alkyl or alkoxy groups mentioned in the definitions of groupsR₂₁, R₂₂ and R₂₃ may each contain 1 to 3 carbon atoms.

As examples of definitions of the groups given hereinbefore:

M may represent an ethylene, 1-methyl-ethylene, 2-methyl-ethylene,1-ethyl-ethylene, 2-ethyl-ethylene, 1,2-dimethyl-ethylene,1,1-dimethyl-ethylene, 1,1-diethyl-ethylene, 1-ethyl-1-methyl-ethylene,2,2-dimethyl-ethylene, 2,2-diethyl-ethylene, 2-ethyl-2-methyl-ethylene,n-propylene, 1-methyl-n-propylene, 2-methyl-n-propylene,3-methyl-n-propylene, 1-ethyl-n-propylene, 2-ethyl-n-propylene,3-ethyl-n-propylene, 1,1-dimethyl-n-propylene, 1,1-diethyl-n-propylene,2,3-dimethyl-n-propylene, 3,3-dimethyl-n-propylene or3-ethyl-3-methyl-n-propylene group,

R₂₁ may represent a thiazolyl, 2-methyl-thiazolyl, 2-ethyl-thiazolyl,2-n-propyl-thiazolyl, 2-chloro-thiazolyl, 2-bromo-thiazolyl,2-trifluoromethyl-thiazolyl, phenyl, fluorophenyl, chlorophenyl,bromophenyl, dichlorophenyl, trifluoromethylphenyl, cyanophenyl,methylphenyl, ethylphenyl, isopropylphenyl, methoxyphenyl, ethoxyphenyl,n-propoxyphenyl, methyl-methoxyphenyl, chloro-methylphenyl,bromo-methylphenyl, chloro-methoxyphenyl, bromo-methoxyphenyl,amino-chlorophenyl, amino-dichlorophenyl, amino-bromophenyl,amino-chloro-fluorophenyl, amino-chloro-bromophenyl,amino-dibromophenyl, amino-cyanophenyl, amino-fluoro-cyanophenyl oramino-cyano-chlorophenyl group,

R₂₂ may represent a hydrogen atom, a thiazolyl, 2-methyl-thiazolyl,2-ethyl-thiazolyl, 2-n-propyl-thiazolyl, 2-chloro-thiazolyl,2-bromo-thiazolyl or 2-trifluoromethyl-thiazolyl group and

R₂₃ may represent a hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy,carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl,isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl,di-n-propylaminocarbonyl, N-ethyl-methylaminocarbonyl,N-ethyl-isopropyl-aminocarbonyl, 2-hydroxy-ethoxy, 3-hydroxy-n-propoxy,4-hydroxy-n-butoxy, 5-hydroxy-n-pentyloxy; 6-hydroxy-n-hexyloxy,7-hydroxy-n-heptyloxy, 2-methoxy-ethoxy, 2-ethoxy-ethoxy,2-n-propoxy-ethoxy, 3-ethoxy-n-propoxy, 4-methoxy-n-butoxy,6-ethoxy-n-hexyloxy, 2-phenethoxy-ethoxy, 2-amino-ethoxy,2-methylamino-ethoxy, 2-dimethylamino-ethoxy, 2-isopropylamino-ethoxy,2-di-n-propylamino-ethoxy, 2-(1-pyrrolidino)ethoxy,2-(1-piperidino)ethoxy, 2-(1-hexamethyleneimino)-ethoxy,3-amino-n-propoxy, 6-amino-n-hexyloxy, 7-methylamino-n-heptyloxy,3-diethylamino-n-propoxy, 3-(1-piperidino)-n-propoxy,4-dimethylamino-n-butoxy, carboxymethoxy, 2-carboxy-ethoxy,3-carboxy-n-propoxy, 4-carboxy-n-butoxy, methoxycarbonylmethoxy,2-methoxycarbonyl-ethoxy, 6-methoxycarbonyl-hexyloxy,ethoxycarbonylmethoxy, 2-ethoxycarbonyl-ethoxy,3-ethoxycarbonyl-n-propoxy, n-propoxycarbonylmethoxy,2-isopropoxycarbonyl-ethoxy, 4-n-propoxycarbonyl-n-butoxy,aminocarbonylmethoxy, 2-aminocarbonyl-ethoxy, 4-aminocarbonyl-n-butoxy,methylamino-carbonylmethoxy, 2-methylaminocarbonyl-ethoxy,dimethylaminocarbonyl-methoxy, 2-dimethyl-aminocarbonyl-ethoxy,4-dimethylaminocarbonyl-n-butoxy, diethylaminocarbonylmethoxy,2-diethylaminocarbonyl-ethoxy, 2-di-n-propylaminocarbonyl-ethoxy,2-carboxy-ethenyl, 2-carboxy-1-methyl-ethenyl,2-carboxy-2-methyl-ethenyl, 2-carboxy-1-ethyl-ethenyl,2-carboxy-1-n-propyl-ethenyl, 2-methoxy-carbonyl-ethenyl,2-methoxycarbonyl-1-methyl-ethenyl, 2-ethoxycarbonyl-ethenyl,2-ethoxycarbonyl-1-methyl-ethenyl or 2-isopropoxycarbonyl-ethenyl group.

In addition to the compounds mentioned in the Examples, the followingcompounds may also be cited, which are covered by general formula XXVIIabove:

N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine,

N-[2-(4-Carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine,

N-[2-(4-(2-Carbomethoxy-1-methyl-ethenyl)-phenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine,

N-[2-(4-(2-Methylamino-ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine,

N-[2-(4-(2-(1-Piperidino)ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine,

N-[3-(4-Carboxamidophenyl)-1-methylpropyl]-2-hydroxy-(2-trifluoromethyl-thiazol-4-yl)morpholine,

N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)morpholine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methyl-ethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)morpholine,

N-[2-(4-(2-Hydroxy-ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)morpholine,

N-[2-(4-(6-Hydroxy-n-hexyloxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)morpholine,

N-[2-(4-Carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)morpholine,

N-[2-(4-(2-Ethoxy-ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)morpholine,

N-[2-(4-(2-(2-Phenylethoxy)ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)morpholine,

N-[2-(4-(2-Carbomethoxy-1-methyl-ethenyl)phenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazol-4-yl)-morpholine,

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)morpholine,

N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-phenyl-morpholine,

N-[2-(4-(2-(2-Phenylethoxy)ethoxy)phenyl)-1-methyl-ethyl]-2-hydroxy-2-phenyl-morpholine,

N-[2-(4-Carbethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine,

N-[2-(4-(6-Hydroxy-n-hexyloxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine,

N-[2-(4-(2-Methylamino-ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine,

N-[2-(4-(2-(1-Piperidino)ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine,

N-[2-(4-(2-(2-Phenylethoxy)ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine,

N-[2-(4-(2-Ethoxy-ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine,

N-[2-(4-(2-Carbomethoxy-1-methyl-ethenyl)phenyl)-1-methylethyl]-2-hydroxy-2-phenyl-morpholine,

N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-methylphenyl)morpholine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-methylphenyl)morpholine,

N-[2-(4-(2-Hydroxy-ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-methylphenyl)morpholine,

N-[2-(4-(6-Hydroxy-n-hexyloxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-methylphenyl)morpholine,

N-[2-(4-(2-(2-Phenylethoxy)ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-methylphenyl)morpholine,

N-[2-(4-(2-(2-Phenylethoxy)ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine,

N-[2-(4-(2-Ethoxy-ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-methylphenyl)morpholine,

N-[2-(4-Carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-methylphenyl)morpholine,

N-[2-(4-(2-Carbomethoxy-1-methyl-ethenyl)phenyl)-1-methylethyl]-2-hydroxy-2-(3-methylphenyl)morpholine,

N-[2-(4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)morpholine,

N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)morpholine,

N-[2-(4-(2-Hydroxy-ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)morpholine,

N-[2-(4-(6-Hydroxy-n-hexyloxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-(3-trifluoromethylphenyl)morpholine,

N-[2-(4-(2-(2-Phenylethoxy)ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)morpholine,

N-[2-(4-(2-Ethoxy-ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)morpholine,

N-[2-(4-Carbethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)morpholine,

N-[2-(4-(2-Carbomethoxy-1-methyl-ethenyl)phenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)-morpholineand

N-[2-(4-(2-Carbomethoxy-1-methyl-ethenyl)phenyl)-1-methylethyl]2-hydroxy-2-(4-amino-3-cyano-5-fluorophenyl)morpholine,

and the optical isomers, diastereomers and acid addition salts thereof.

However, the preferred compounds of general formula XXVII are thosewherein

M represents an ethylene or n-propylene group optionally substituted bya methyl group,

R₂₁ represents a thiazolyl group optionally substituted in the2-position by a halogen atom or by a trifluoromethyl or methyl group, aphenyl group optionally substituted by a halogen atom or by atrifluoromethyl, methyl or methoxy group, or an aminophenyl group whichis substituted by a cyano group, a halogen atom, two halogen atoms or bya halogen atom and a cyano group,

R₂₂ represents a hydrogen atom or a thiazolyl group optionallysubstituted in the 2-position by a halogen atom or by a trifluoromethylor methyl group, and

R₂₃ represents a hydroxy, methoxy, carboxy, methoxycarbonyl,ethoxycarbonyl, aminocarbonyl, carboxymethoxy, methoxycarbonylmethoxy,ethoxycarbonylmethoxy, aminocarbonylmethoxy, methylaminocarbonylmethoxy,2-hydroxy-ethoxy, 2-ethoxy-ethoxy, 2-phenethoxy-ethoxy,2-(1-piperidino)ethoxy, 6-hydroxy-n-hexyloxy or2-carbomethoxy-1-methyl-ethenyl group, and the optical isomers,diastereomers and acid addition salts thereof.

However, particularly preferred compounds are the compounds of generalformula ##STR30## wherein R₂₁ represents a thiazol-4-yl groupsubstituted in the 2-position by a chlorine atom or by atrifluoro-methyl group, a phenyl group optionally substituted by achlorine atom or by a trifluoromethyl or methyl group, or a4-amino-3-fluoro-5-cyano-phenyl group,

R₂₂ represents a hydrogen atom and

R₂₃ represents a carboxymethoxy, carbomethoxy-methoxy,ethoxycarbonylmethoxy, aminocarbonyl-methoxy,methylaminocarbonylmethoxy, 2-ethoxy-ethoxy, 2-hydroxy-ethoxy or2-carbomethoxy-1-methyl-ethenyl group, and the optical isomers,diastereomers and acid addition salts thereof.

According to the invention, the new compounds are obtained by thefollowing process:

Reaction of a compound of general formula

    R.sub.21 --CO--CH.sub.2 --Z.sub.1                          (XXVIII)

wherein

R₂₁ is defined as hereinbefore and

Z₁ represents a nucleophilic leaving group, with an amine of generalformula ##STR31## wherein M, R₂₂ and R₂₃ are defined as hereinbefore.

Examples of nucleophilic leaving groups include halogen atoms orsulphonyloxy groups, e.g. a chlorine, bromine or iodine atom or amethanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group.

The reaction is appropriately carried out in a suitable solvent such asacetone, methylene chloride, tetrahydrofuran or dioxan and preferably inthe presence of an acid binding agent such as potassium hydrogencarbonate, potassium carbonate, sodium hydrogen carbonate, sodiumcarbonate, triethylamine, pyridine or in an excess of the amine ofgeneral formula XXIX used, whilst the organic binding agents maysimultaneously also be used as solvent, at temperatures of between 0°and 100° C. preferably at temperatures of between 5° and 50° C.

It may also be advantageous for any reactive groups such as hydroxy,carboxy, amino or alkylamino groups, but particularly amino oralkylamino groups, to be protected during the reaction by conventionalprotecting groups.

Examples of protecting groups for a hydroxy group include the benzyl,benzyloxycarbonyl, tetrahydro-pyranyl, trimethylsilyl andtert.butyldimethylsilyl groups,

protecting groups for a carboxy group include the benzyl, tert.butyl,trimethylsilyl and benzyloxymethyl groups and

protecting groups for an amino or alkylamino group include the acetyl,benzoyl, tert.butoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl andbenzyl groups.

The optional subsequent cleavage of any protecting group used ispreferably carried out hydrolytically in an aqueous solvent, e.g. inwater, isopropanol/water, tetrahydrofuran/water or dioxan/water, in thepresence of an alkali metal base such as sodium hydroxide or potassiumhydroxide or an acid such as hydrochloric, sulphuric or trifluoro-aceticacid at temperatures of between 0° and 100° C., preferably attemperatures of between 20° and 50° C.

If according to the invention a compound of general formula XXVII isobtained wherein R₂₃ represents or contains an alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, thismay be converted by hydrolysis into a corresponding compound of generalformula XXVII wherein R₂₃ represents or contains a carboxy group, or

if a compound of general formula XXVII is obtained wherein R₂₃represents or contains an alkoxycarbonyl group, this may be converted byamidation into a corresponding compound of general formula XXVII whereinR₂₃ represents or contains an aminocarbonyl, alkylaminocarbonyl ordialkylaminocarbonyl group.

Subsequent hydrolysis is carried out in the presence of a base such assodium hydroxide or potassium hydroxide in a suitable solvent such aswater, methanol, ethanol, ethanol/water, water/isopropanol orwater/dioxan at temperatures of between -10° C. and 100° C., e.g. attemperatures of between ambient temperature and 50° C.

Subsequent amidation is carried out in a suitable inert solvent such asdiethyl ether, tetrahydrofuran, dioxan or in an excess of the amineused, optionally in a pressurised vessel at temperatures of between 0°and 100° C. but preferably at temperatures of between 20° and 80° C.

As already mentioned hereinbefore, the new compounds may occur in theform of their enantiomers, mixtures of enantiomers or racemates or, ifthey contain at least 2 asymmetric carbon atoms, in the form of theirdiastereomers or mixtures of diastereomers.

Thus, the compounds of general formula XXVII obtained which contain onlyone optically active centre may be resolved by known methods (seeAllinger N. L. and Elich W. L. in "Topics in Stereochemistry", Vol. 6,Wiley Interscience, 1971) into their optical enantiomers, e.g. byrecrystallisation from an optically active substance which forms a saltwith the racemic compound, particularly an acid, and separating theresultant salt mixture, e.g. by means of the differential solubilities,into the diastereomeric salts from which the free enantiomers can beliberated by the use of suitable reagents. Examples of optically activeacids in common use include the D and L forms of tartaric acid,di-o-toluoyltartaric acid, malic acid, mandelic acid, camphorsulphonicacid, glutamic acid, aspartic acid and quinic acid.

Furthermore, the compounds of general formula XXVII obtained having atleast 2 asymmetric carbon atoms may be resolved into their diastereomerson the basis of their physical/chemical differences using known methods,e.g. by chromatography and/or fractional crystallisation. A pair ofenantiomers thus obtained may subsequently be resolved into theiroptical antipodes as described above. If for example a compound ofgeneral formula I contains two optically active carbon atoms thecorresponding (R R', S S') and (R S', S R') forms are obtained.

The compounds of general formulae XXVIII and XXIX used as startingmaterials may be obtained by methods known per se.

Thus, for example, a corresponding thiazole derivative of generalformula XXVIII is obtained by bromination of the corresponding acetylcompounds in glacial acetic acid or hydrogen bromide/glacial acetic acidat temperatures of between 20° and 100° C. or by cyclisation of thecorresponding thioamides with dibromodiacetyl in a solvent such asdiethyl ether, acetonitrile or toluene.

A compound of general formula XXIX used as starting material may, ofcourse, also be used in its optically pure form.

Moreover, the compounds of general formula XXVII obtained may beconverted into their acid addition salts, particularly, forpharmaceutical use, their physiologically acceptable salts withinorganic or organic acids. Examples of acids include hydrochloric,hydrobromic, sulphuric, phosphoric, fumaric, succinic, lactic, citric,tartaric and maleic acid.

As already mentioned hereinbefore, the new compounds of general formulaXXVII, the enantiomers, mixtures of enantiomers or, if they have atleast 2 asymmetric carbon atoms, the diastereomers or mixtures ofdiastereomers and the acid addition salts thereof, particularly thephysiologically acceptable acid addition salts for pharmaceutical use,have valuable pharmacological properties, particularly an effect onmetabolism, preferably the effect of lowering blood pressure andreducing body fat and the effect of lowering the atherogeniclipoproteins VLDL and LDL. Moreover, some of the compounds mentionedabove also have an anabolic activity.

For example, the following compounds were investigated for theirbiological properties as follows:

AA=N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine,

BB=N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methyl-ethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine,

CC=N-[2-(4-(2-Hydroxy-ethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholineand

DD=N-[2-(4-Carbomethoxtmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

1. Antidiabetic activity:

The antidiabetic activity of the compounds according to the inventioncan be measured as a blood sugar-lowering activity in experimentalanimals. The test substances are suspended in 1.5% methylcellulose andadministered by stomach tube to female mice bred by the applicants. 30minutes later 1 g of glucose per kg of body weight is dissolved in waterand administered subcutaneously. Another 30 minutes later blood is takenfrom the retroorbital venous plexus. From the serum, the amount ofglucose is determined by the hexokinase method using an analyticalphotometer.

The following Table shows the lowering of blood pressure observed inthis test, given as a percentage of a control group conducted inparallel. Statistical evaluation is carried out using the Student t testtaking p=0.05 as the limit of significance.

    ______________________________________                                                 % change from the level of the control group                                  Dosage [mg/kg]                                                       Compound   0.1           0.3    1                                             ______________________________________                                        AA         -55           -65    -65                                           BB         -39           -55    -67                                           CC         -21           -58    -63                                           DD         -13           -35    -49                                           ______________________________________                                    

2. Anti-obesity activity:

To determine the anti-obesity activity of the compounds according to theinvention the increase in lipolysis is measured by the increase in theglycerine in the serum. The design of the test is identical to the testdescribed above for testing the effect of lowering blood sugar.Glycerine is determined in a combined enzymatic/colorimetric test usingan analytical photometer. The results are given in the following Tableas a percentage of a control group conducted in parallel.

    ______________________________________                                                 % change from the level of the control group                                  Dosage [mg/kg]                                                       Compound   0.1           0.3    1                                             ______________________________________                                        AA         296           456    552                                           BB         267           280    353                                           CC         224           574    652                                           DD          77           217    330                                           ______________________________________                                    

Moreover, in the tests on the substances according to the inventioncarried out as described above no effects on circulation were observedat the dosages used and no toxic side effects were observed at dosagesup to 30 mg/kg p.o. These substances are therefore well tolerated.

In view of their pharmacological properties the new compounds of generalformula XXVII and the physiologically acceptable acid addition saltsthereof with organic or inorganic acids are therefore suitable for thetreatment of both diabetes mellitus and also obesity, and henceparticularly for the treatment of obese diabetics. Moreover, the newcompounds may be used for the prevention and treatment ofatherosclerotic changes in the blood vessels, which occur particularlyin diabetics. The dosage required can be matched entirely to themetabolic-physiological requirements of the individual patient since thecompounds are free from effects on the heart and circulation over a widedosage range. In adults, therefore, the daily dosage is between 1 and3000 mg, preferably from 1 to 1000 mg, divided into 1 to 4 doses perday. For this purpose, the compounds mentioned above, optionallycombined with other active substances, may be incorporated in theconventional galenic preparations such as powders, plain and coatedtablets, capsules, suppositories and suspensions.

Furthermore, the compounds mentioned above may be used for the treatmentof fat animals and, as a consequence of their body fat-reducing(lipolytic) activity, they may be used for the reduction of undesirablefat deposits in animal rearing, i.e. to improve the quality of the meatof fattened animals such as pigs, cattle, sheep and poultry. In animals,the compounds mentioned above may be administered orally or non-orally,e.g. as a feed additive or by injection or by means of implantedminipumps. The daily dosage ranges from 0.01 to 100 mg/kg, butpreferably from 0.1 to 10 mg/kg of body weight.

The Examples which follow are intended to illustrate the invention:

Example AA

2-Trifluoromethyl-4-bromoacetyl-thiazole

9.2 g (0.071 mol) of trifluorothioacetamide dissolved in 200 ml ofacetonitrile is added dropwise, over 2.5 hours, to a boiling solution of17.4 g (0.071 mol) of dibromodiacetyl in 200 ml of acetonitrile. Thesolvent is distilled off and the product remaining is extracted withcyclohexane. The extract is evaporated down and the oily residueremaining is purified over a silica gel column using toluene/cyclohexaneas eluant.

Yield: 8.2 g (42.7% of theory),

15 M.p.: 36°-37° C.

Example BB

2-Chloro-4-bromoacetyl-thiazole

7.6 g (6.0344 mol) of 2-amino-4-bromoacetyl-thiazole is dissolved in 20ml of water and 50 ml of concentrated hydrochloric acid. At 0° C., withstirring, a solution of 3.44 g (0.05 mol) of sodium nitrite in 15 ml ofwater is added dropwise. Then the diazonium salt solution formed isadded in batches, with vigorous stirring, to a cold solution of 4.93 g(0.05 mol) of copper(I)chloride in 15 ml of concentrated hydrochloricacid and the mixture is stirred at ambient temperature for 20 hours. Itis then diluted with 100 ml of water and extracted with ether. The etherextract is dried over sodium sulphate and evaporated down. Forpurification the crude product is purified over a silica gel columnusing methylene chloride as eluant.

Yield: 4 g (48% of theory),

M.p.: 72° C.

    ______________________________________                                        Calculated:  C 24.96    H 1.25    N 5.82                                      Found:       25.12      1.30      6.00                                        ______________________________________                                    

Example CC

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine(pair of diastereomers A)

1.27 g (6.0 mmol) of2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine and 1.33 g (6.0mmol) of (4-carbomethoxymethoxy)phenyl acetone are dissolved in 40 ml ofabsolute methanol, 0.34 ml (6.0 mmol) of glacial acetic acid and 0.37 g(6.0 mmol) of sodium cyanoborohydride are added and the mixture isstirred for 5 hours at ambient temperature. It is then poured onto ice,acidified with hydrochloric acid, made alkaline with sodium hydrogencarbonate solution and extracted with chloroform. The extracts are driedand purified by column chromatography on silica gel (eluant: methylenechloride/methanol =20:1). An approximately 50:50 diastereomeric mixtureof the base is obtained. This is recrystallised from a mixture of etherand ethyl acetate =65:10 and then recrystallised twice more from ethylacetate. The pair of diastereomers A is obtained in 98-99% purity.

Yield: 14% of theory,

M.p.: 104°-105° C.

    ______________________________________                                        Calculated:  C 51.66    H 5.06    N 6.70                                      Found:       51.90      4.82      6.82                                        ______________________________________                                    

¹ H NMR spectrum (400 MHz) (CDCl₃ /CD₃ OD): δ=7.59 ppm (s, 1H)

Example 118

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine

1.1 g (4.1 mmol) ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-ethanamineis stirred together with 0.95 g (4.1 mmol) of 3-chloro-phenacyl bromideand 1.2 g (12.3 mmol) of potassium hydrogen carbonate in 30 ml ofacetone for 24 hours at ambient temperature. The mixture is thenfiltered, evaporated down and the evaporation residue is purified bycolumn chromatography on silica gel (eluant: toluene/ethyl acetate=2:1).

15 Yield: 1.0 g (57% of theory),

M.p.: <20° C.

    ______________________________________                                        Calculated:                                                                              C 62.93   H 6.24   N 3.33  Cl 8.44                                 Found:     62.71     6.13     3.22    8.57                                    ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃): δ=0.97 ppm (d)=--CH--CH₃ δ=0.99 ppm(d)=--CH--CH₃

The following are prepared analogously to Example 118:

118a)N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine

from 3-chloro-phenacyl bromide andN-[2-(4-2-hydroxyethoxy)phenyl)-1-methylethyl]-2-hydroxyethanamine.

Yield: 50.6% of theory,

M.p.: <20° C.

    ______________________________________                                        Calculated:                                                                              C 64.36   H 6.69   N 3.57  Cl 9.05                                 Found:     64.26     6.57     3.41    9.37                                    ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=0.98 ppm (d)=--CH--CH₃δ=1.00 ppm (d)=--CH--CH₃

118b)N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine

from 3-chloro-phenacyl bromide andN-[2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxyethanamine.

Yield: 53.7% of theory,

M.p.: <20° C.

    ______________________________________                                        Calculated:                                                                              C 63.07   H 6.50   N 6.69  Cl 8.46                                 Found:     62.88     6.41     6.57    8.58                                    ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=0.98 ppm (d)=--CH--CH₃δ=1.01 ppm (d)=--CH--CH₃

118c)N-[2-(4-Carbomethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-trifluoromethylphenyl)morpholine

from 3-trifluoromethyl-phenacyl bromide andN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxyethanamine.

Yield: 56% of theory,

M.p.: <20° C.

    ______________________________________                                        Calculated:  C 60.92    H 5.78    N 3.09                                      Found:       61.13      5.92      2.93                                        ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=0.98 ppm (d)=--CH--CH₃δ=1.00 ppm (d)=--CH--CH₃

118d)N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-phenyl-morpholine

from phenacyl bromide andN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-ethanamine.

Yield: 52.9% of theory,

M.p.: <20° C.

    ______________________________________                                        Calculated:  C 68.55    H 7.86    N 3.63                                      Found:       68.71      7.13      3.57                                        ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=0.96 ppm (d)=--CH--CH₃δ=0.99 ppm (d)=--CH--CH₃

118e)N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-methylphenyl)morpholine

from 3-methyl-phenacyl bromide andN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxyethanamine.

Yield: 59.6% of theory,

M.p.: <20° C.

    ______________________________________                                        Calculated:  C 69.15    H 7.32    N 3.51                                      Found:       69.12      7.38      3.35                                        ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=0.97 ppm (d)=--CH--CH₃δ=0.99 ppm (d)=--CH--CH₃

118f)N-[2-(4Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

fromN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-ethamine and2-trifluoromethyl-4-bromoacetyl-thiazole.

Yield: 49% of theory,

M.p.: <20° C.

    ______________________________________                                        Calculated:  C 52.16    H 5.03    N 6.09                                      Found:       52.37      5.36      5.87                                        ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of 5 the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=7.67 ppm (s, 0.5H) δ=7.72ppm (s, 0.5H)

118g)N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-chloro-thiazole-4-yl)-morpholine

fromN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-ethanamineand 2-chloro-4-bromoacetyl-thiazole.

Yield: 56% of theory,

M.p.: <20° C.

    ______________________________________                                        Calculated:  C 53.45    H 5.42    N 6.56                                      Found:       53.20      5.67      6.22                                        ______________________________________                                    

According to ¹ H NMR there is a 40:60 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=7.39 ppm (s, 0.4H) δ=7.42ppm (s, 0.6H)

118h)N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-morpholine

fromN-[2-(4-(2-hydroxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-ethanamine and2-trifluoromethyl-4-bromoacetyl-thiazole.

Yield: 20% of theory,

M.p.: <20° C.

    ______________________________________                                        Calculated:  C 54.80    H 5.57    N 6.73                                      Found:       54.65      5.64      6.64                                        ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=7.80 ppm (s, 0.5H) δ=7.74ppm (s, 0.5H)

118i)N-[2-(4-Methylaminocarbonylmethoxyphenyl)-1-methyl-ethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

fromN-[2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-ethanamineand 2-trifluoromethyl-4-bromoacetyl thiazole.

Yield: 45.6% of theory,

M.p.: <20° C.

    ______________________________________                                        Calculated:  C 52.28    H 5.26    N 9.14                                      Found:       52.17      5.23      9.18                                        ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=7.81 ppm (s, 0.5H) δ=7.77ppm (s, 0.5H)

118k)N-[2-(4-(6-Hydroxy-n-hexyloxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

from 2-trifluoromethyl-4-bromoacetyl-thiazole andN-[2-(4-(6-hydroxy-hexyloxy)phenyl)-1-methylethyl]-2-hydroxy-ethanamine.

Yield: 45% of theory,

M.p.: <20° C.

    ______________________________________                                        Calculated:  C 56.54    H 6.40    N 5.73                                      Found:       56.67      6.37      5.66                                        ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=7.80 ppm (s, 0.5H) δ=7.78ppm (s, 0.5H)

118l)N-[2-(4-2-Carbomethoxy-1-methyl-ethenyl)phenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine

from 3-chloro-phenacyl bromide andN-[2-(4-(2-carbomethoxy-1-methyl-ethenyl)phenyl)-1-methylethyl]-2-hydroxy-ethanamine.

Yield: 50% of theory,

M.p.:<20° C.

    ______________________________________                                        Calculated:                                                                              C 67.05   H 6.56   N 3.26  Cl 8.25                                 Found:     67.12     6.56     3.27    8.44                                    ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=1.01 ppm (d)=--CH--CH₃δ=1.03 ppm (d)=--CH--CH₃

118m)N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(4-amino-3-cyano-5-fluoro-phenyl)morpholine

from 4-amino-3-cyano-5-fluoro-phenacyl bromide andN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-ethanamine.

Yield: 47% of theory,

M.p.:<20° C.

    ______________________________________                                        Calculated:  C 62.29    H 5.91    N 9.48                                      Found:       62.28      5.93      9.30                                        ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=0.965 ppm (d)=--CH--CH₃δ=0.985 ppm (d)=--CH--CH₃

118n)N-[2-(4-(2-Ethoxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

from N-[2-(4-(2-ethoxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-ethanamineand 2-trifluoromethyl-4-bromoacetyl-thiazole.

Yield: 52% of theory,

M.p.:<20° C.

    ______________________________________                                        Calculated:  C 54.77    H 5.91    N 6.08                                      Found:       54.68      6.00      5.97                                        ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=7.80 ppm (s, 0.5H) δ=7.73ppm (s, 0.5H)

Example 119

N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-methylphenyl)morpholine

0.5 g (1.25 mmol) ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-methylphenyl)morpholineis dissolved in 5 ml of ethanol and after the addition of 3 ml of 1Nsodium hydroxide solution the mixture is stirred at ambient temperature(about 1 hour) until the chromatograph shows that there is no startingmaterial left. Then it is neutralised by the addition of 3 ml of 1Nhydrochloric acid and extracted with chloroform. The extracts are dried,concentrated by evaporation and the evaporation residue is purified bycolumn chromatography on silica gel (eluant: ethyl acetate/methanol=2:1).

Yield: 0.32 g (66% of theory),

M.p.: 137°-140° C.

    ______________________________________                                        Calculated:  C 68.55    H 7.06    N 3.63                                      Found:       68.41      7.12      3.44                                        ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=0.975 ppm (d)=--CH--CH₃δ=0.995 ppm (d)=--CH--CH₃

Analogously to Example 119 the following are prepared:

119a)N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine

fromN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine.

Yield: 26.3% of theory,

M.p.: 90°-95° C.

    ______________________________________                                        Calculated:                                                                              C 62.14   H 5.96   N 3.45  Cl 8.73                                 Found:     62.13     5.89     3.28    8.65                                    ______________________________________                                    

According to ¹ H NMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃): δ=0.99 ppm (d)=--CH--CH₃ δ=1.02 ppm(d)=--CH--CH₃

119b)N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine

fromN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)morpholine.

Yield: 50% of theory,

M.p.: 80° C.

    ______________________________________                                        Calculated:  C 51.11    H 4.74    N 6.28                                      Found:       50.82      4.63      6.16                                        ______________________________________                                    

According to ¹ H NMR there is a 40:60 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=7.94 ppm (s, 0.4H) δ=7.98ppm (s, 0.6H)

Example 120

N-[2-4-Aminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine

2.03 g (4.76 mmol) ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholineis dissolved in 20 ml of ammonia-saturated methanol and stirred for 24hours at ambient temperature. The mixture is then evaporated down andthe evaporation residue is purified by column chromatography on silicagel (eluant: ethyl acetate/cyclohexane =3:1).

Yield: 810 mg (42.6% of theory),

M.p.:<20° C.

    ______________________________________                                        Calculated:  C 62.30    H 6.22    N 6.92                                      Found:       62.21      6.25      6.87                                        ______________________________________                                    

According to ¹ H HMR there is a 50:50 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=0.98 ppm (d)=--CH--CH₃δ=1.01 ppm (d)=--CH--CH₃

Example 121

N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-phenyl-6-(2-trifluoromethyl-thiazol-4-yl)morpholine

To a suspension of 0.38 g (0.9 mmol) ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine[pair of diastereomers A] and 0.27 g (2.7 mmol) of potassium hydrogencarbonate in 4 ml of acetone, 0.18 g (0.9 mmol) of phenacyl bromide isadded and stirred for 50 hours at ambient temperature. The mixture isthen evaporated to dryness and the base is purified over a silica gelcolumn using toluene/ethyl acetate 8:2 as eluant.

Yield: 0.15 g (31% of theory),

M.p.:<20° C.

    ______________________________________                                        Calculated:  C 58.20    H 5.07    N 5.22                                      Found:       57.95      5.14      5.08                                        ______________________________________                                    

According to ¹ H NMR spectrum there is a 20:80 mixture of thediastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=1.00 ppm (d, 0.8H)=--CH--CH₃δ=1.05 ppm (d, 0.2H)=--CH--CH₃

The following are prepared analogously to Example 121:

121a)N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)-6-(2-trifluoromethyl-thiazol-4-yl)morpholine

fromN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine(pair of diastereomers A) with 3-chloro-phenacyl bromide and potassiumhydrogen carbonate in acetone.

Yield: 73% of theory,

M.p.:<20° C.

    ______________________________________                                        Calculated:  C 54.68    H 4.59    N 4.91                                      Found:       54.79      4.52      4.77                                        ______________________________________                                    

According to ¹ H NMR there is a 96:4 mixture of the diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=1.01 ppm (d,0.96H)=--CH--CH₃ δ=1.05 ppm (d, 0.04H)=--CH--CH₃

121b)N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2,6-bis(2-trifluoromethyl-thiazol-4-yl)morpholine

fromN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine(pair of diastereomers A) with 2-trifluoromethyl-4-bromoacetyl-thiazoleand potassium hydrogen carbonate in acetone.

Yield: 65% of theory,

M.p.:<20° C.

    ______________________________________                                        Calculated:  C 47.13    H 3.79    N 6.87                                      Found:       46.97      3.78      6.68                                        ______________________________________                                    

According to ¹ H NMR spectrum there is a pair of diastereomers.

400 MHz ¹ H NMR spectrum (CDCl₃ /CD₃ OD): δ=1.035 ppm (d)=--CH--CH₃

Example 122

Coated tablet containing 10 mg ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl?-2-hydroxy-2-(3-chlorophenyl)morpholine

Composition:

1 coated tablet contains:

    ______________________________________                                        (1) Active substance                                                                             10.0 mg                                                    (2) Lactose        69.0 mg                                                    (3) Corn starch    35.0 mg                                                    (4) Polyvinylpyrrolidone                                                                          5.0 mg                                                    (5) Magnesium stearate                                                                            1.0 mg                                                                       120.0 mg                                                   ______________________________________                                    

Method

(1)+(2)+(3) are mixed together and moistened with (4) in an aqueoussolution. The moist mass is passed through a screen with a mesh size of1.6 mm and dried at 45° C. in a circulating air dryer. The dry granulesare passed through a 1 mm mesh screen and mixed with (5). The finishedmixture is compressed to form tablet cores.

Weight of core: 120.0 mg

Diameter: 7.0 mm

Radius of curvature: 6.0 mm

The tablet cores thus produced are coated in known manner with a coatingconsisting essentially of sugar and talc. This coating may also containdye extracts. The finished coated tablets are polished with wax.

Weight of coated tablet: 180.0 mg

Example 123

Coated tablet containing 50 mg of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl?-2-hydroxy-2-(3-chloro phenyl)morpholine

Composition:

1 coated tablet contains:

    ______________________________________                                        (1) Active substance                                                                             50.0 mg                                                    (2) Lactose        110.8 mg                                                   (3) Corn starch    50.0 mg                                                    (4) Polyvinylpyrrolidone                                                                          8.0 mg                                                    (5) Magnesium stearate                                                                            1.2 mg                                                                       220.0 mg                                                   ______________________________________                                    

Method

The method is analogous to that of Example 122.

Weight of core: 220.0 mg

Diameter: 9.0 mm

Radius of curvature: 8.0 mm

Weight of coated tablet: 300.0 mg

Example 124

Tablets containing 150 mg of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine

Composition:

1 tablet contains

    ______________________________________                                        (1) Active substance 150.0 mg                                                 (2) Lactose          86.0 mg                                                  (3) Corn starch      50.8 mg                                                  (4) Microcrystalline cellulose                                                                     25.0 mg                                                  (5) Polyvinylpyrrolidone                                                                            7.0 mg                                                  (6) Magnesium stearate                                                                              1.2 mg                                                                       320.0 mg                                                 ______________________________________                                    

Method

(1)+(2)+(3)+(4)+(5) are mixed together and moistened with water. Themoist mass is passed through a 1.6 mm mesh screen and dried at 45° C.The dry granules are passed through the same screen again and mixed with(6). Tablets are compressed from the finished mixture.

Weight of tablet: 320.0 mg

Diameter: 10.0 mm

The tablets are provided with a dividing notch to make it possible tobreak them in half.

Example 125

Hard gelatin capsules containing 100 mg ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine

Composition:

1 capsule contains:

Capsule shell: hard gelatin capsules size 3

    ______________________________________                                        Capsule contents:                                                             ______________________________________                                        (1) Active substance                                                                             100.0 mg                                                   (2) Lactose × 1H.sub.2 O                                                                   38.0 mg                                                    (3) Dried corn starch                                                                            60.0 mg                                                    (4) Magnesium stearate                                                                            2.0 mg                                                    Weight of capsule filling:                                                                       200.0 mg                                                   (5) Distilled water                                                                              q.s.                                                       ______________________________________                                    

Method

A small amount of lactose is dissolved in a quantity of about 10% indistilled water (granulating liquid). The active substance, theremaining lactose and the corn starch are mixed together and moistenedwith the granulating liquid. The mass is screened and dried and, afterbeing screened once more, homogeneously mixed with magnesium stearate.The fine granules are packed into capsules in a suitable machine.

Example 126

Hard gelatin capsules containing 200 mg ofN-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine

Composition:

Capsule shell: hard gelatin capsules size 1

    ______________________________________                                        Capsule contents:                                                             ______________________________________                                        (1) Active substance                                                                             200.0 mg                                                   (2) Lactose × 1H.sub.2 O                                                                   47.0 mg                                                    (3) Dried corn starch                                                                            70.0 mg                                                    (4) Magnesium stearate                                                                            3.0 mg                                                    Weight of capsule filling:                                                                       320.0 mg                                                   (5) Distilled water                                                                              q.s.                                                       ______________________________________                                    

Method

A small amount of lactose is dissolved in a concentration of about 10%in distilled water (granulating liquid). The active substance, theremaining lactose and corn starch are mixed together and moistened withthe granulating liquid. The mass is screened and dried and after beingscreened once more is homogeneously mixed with magnesium stearate. Thefine granules are packed into capsules in a suitable machine.

What is claimed is:
 1. A compound of formula: ##STR32## in which A isn-alkylene of 2 to 3 carbons, optionally mono- or disubstituted withmethyl or ethyl,R₁ is selected from the group consisting of hydrogen,fluoro, chloro, bromo, trifluoromethyl, alkyl, phenyl, piperidino,amino, alkylamino, dialkylamino, alkanoylamino and benzoylamino, R₂ ishydrogen or alkyl, R₃ together with R₄ is alkoxycarbonylmethylene, andR₅ is selected from the group consisting of hydroxyl, alkoxy, carboxyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkoxy having 1 to 6 carbons and substituted by a terminal memberselected from the group consisting of carboxyl, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl, alkoxyhaving 2 to 7 carbons and substituted by a terminal member selected fromthe group consisting of hydroxyl, alkoxy, phenylalkoxy, amino,alkylamino and dialkylamino, and alkenylene optionally substituted byalkyl and substituted by a terminal member selected from the groupconsisting of carboxyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl and dialkylaminocarobnyl, wherein said alkyl, alkoxyand alkanoyl each contain, unless indicated otherwise, 1 to 3 carbons,and said alkenyl contains 3 to 5 carbons, and the optical isomers anddiastereomers thereof and physiologically acceptable acid addition saltsthereof with inorganic acids.
 2. The compound as recited in claim 1wherein:A is ethylene or n-propylene, optionally substituted by methyl,R₁ is selected from the group consisting of hydrogen, chloro, alkyl,trifluoromethyl, phenyl, amino, methylamino, dimethylamino, acetylaminoand benzoylamino, R₂ is hydrogen or methyl, R₃ together with R₄ ismethoxycarbonylmethylene, and R₅ is selected from the group consistingof hydroxy, methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl,aminocarbonyl, carboxymethoxy, methoxycarbonylmethoxy,ethoxycarbonylmethoxy, aminocarbonylmethoxy, methylaminocarbonylmethoxy,2-hydroxyethoxy, 2-ethoxyethoxy, 2-phenethoxyethoxy, 2-aminoethoxy,2-methylaminoethoxy, 6-hydroxy-n-hexoxy and2-carbomethoxy-1-methyl-ethenyl, and the optical isomers anddiastereomers thereof and physiologically acceptable acid addition saltsthereof with inorganic or organic acids.
 3. A compound of formula##STR33## in which R₁ is selected from the group consisting of chloro,methyl and trifluoromethyl,R₃ together with R₄ ismethoxycarbonylmethylene, R₅ is selected from the group consisting ofcarboxymethoxy, carbomethoxymethoxy, ethoxycarbonylmethoxy,aminocarbonylmethoxy, methylaminocarbonylmethoxy, 2-methylaminoethoxy,2-hydroxyethoxy and 2-carbomethoxy-1-methylethenyl, and the opticalisomers and diastereomers thereof and physiologically acceptable acidaddition salts thereof with inorganic or organic acids.
 4. Methyl3-[2-(4-(2-carbomethoxy-1-methylethenyl)-phenyl)-1-methylethyl]-5-(2-trifluoromethyl-thiazol-4-yl)-2-oxazolidinecarboxylate, or the optical isomer, diastereomer or physiologicallyacceptable acid addition salt thereof.